{"gene":"IL5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1988,"finding":"Murine IL-5/TRF cDNA encodes a 133-amino-acid precursor; the secreted form is a homodimeric glycoprotein (~46 kDa, comprising ~25–30 kDa subunits) that triggers activated B cells for terminal differentiation into Ig-secreting cells (IgM, IgG1, IgA) and promotes B cell growth and IL-2 receptor induction.","method":"cDNA cloning, recombinant protein expression, functional B-cell differentiation assays, immunoprecipitation with specific mAbs","journal":"Immunological reviews","confidence":"High","confidence_rationale":"Tier 1 / Strong — molecular cloning combined with direct functional reconstitution and antibody neutralization, foundational characterization replicated across multiple assays in the same study","pmids":["3284812"],"is_preprint":false},{"year":1988,"finding":"IL-5 acts specifically on mIgA-positive Peyer's patch B cells to promote terminal differentiation into IgA-secreting cells without driving cell proliferation, establishing that IL-5 is a differentiation (not proliferation) factor acting downstream of IgA isotype switching.","method":"Cell sorting of mIgA+ vs mIgA- B cells, rIL-5 stimulation, ELISPOT assay, [3H]thymidine incorporation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution with purified cell subsets and multiple orthogonal readouts (IgA secretion, ELISPOT, proliferation assay)","pmids":["3258891"],"is_preprint":false},{"year":1988,"finding":"Recombinant EDF (IL-5) expressed in CHO cells retains its dimeric structure and biological activity identical to natural EDF, confirming the homodimeric architecture is sufficient for function.","method":"Recombinant expression in CHO DHFR- cells, methotrexate selection, biochemical characterization of secreted protein","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution in CHO cells with activity confirmation, single study","pmids":["3348775"],"is_preprint":false},{"year":1991,"finding":"Human eosinophils express a single class of high-affinity IL-5 receptor (Kd ~170–330 pM; ~260–380 sites/cell) with a molecular mass of 55–60 kDa identified by affinity cross-linking; IL-5 binding is inhibited by excess unlabeled IL-5 or anti-IL-5 mAb but not by other cytokines, demonstrating receptor specificity.","method":"Radiolabeled IL-5 binding assay, Scatchard analysis, affinity cross-linking, competition binding","journal":"Cellular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct receptor characterization with multiple biophysical and biochemical methods in a single focused study","pmids":["2015632"],"is_preprint":false},{"year":1992,"finding":"The high-affinity receptors for IL-5, IL-3, and GM-CSF are heterodimers composed of a cytokine-specific α subunit and a shared common β subunit; the β subunit is required both for high-affinity ligand binding and for signal transduction, including tyrosine phosphorylation and Ras protein activation. In humans, a single common β subunit is shared among all three receptors.","method":"Molecular cloning of receptor subunits, reconstitution of high-affinity receptors, signal transduction assays","journal":"International journal of cell cloning","confidence":"High","confidence_rationale":"Tier 1 / Strong — receptor reconstitution and signaling assays, replicated across multiple cytokine receptor systems","pmids":["1613263"],"is_preprint":false},{"year":1994,"finding":"IL-5 is a homodimeric glycoprotein that signals through a heterodimeric receptor comprising a unique IL-5-specific α chain (required for ligand binding) and a common β chain shared with IL-3R and GM-CSFR (required for high-affinity binding and signaling).","method":"Biochemical characterization, receptor reconstitution studies","journal":"International archives of allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive receptor characterization review citing reconstitution data, consistent with independent studies","pmids":["7950399"],"is_preprint":false},{"year":1995,"finding":"IL-5 activates the JAK2–STAT1 signaling pathway in human eosinophils: JAK2 is tyrosine-phosphorylated within 1–3 min of IL-5 stimulation, physically associates (co-precipitates) with the β subunit of the IL-5 receptor, and STAT1 (p91) is subsequently tyrosine-phosphorylated and translocates to the nucleus to bind the gamma-activating sequence.","method":"Immunoprecipitation, immunoblotting for tyrosine phosphorylation, JAK2 autophosphorylation assay, co-IP of JAK2 with IL-5Rβ, EMSA with anti-STAT1 supershift","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods (co-IP, kinase assay, EMSA) in a single rigorous study","pmids":["7602114"],"is_preprint":false},{"year":1995,"finding":"IgE-dependent activation of human lung mast cells (via FcεRI crosslinking) induces IL-5 mRNA expression within 2 h (persisting 48–72 h) and release of immunoreactive IL-5 protein (~731 pg/10^6 cells over 48 h), identifying mast cells as a non-T-cell source of IL-5.","method":"RT-PCR, in situ hybridization, double in situ hybridization-immunocytochemistry, ELISA; purified mast cells (>93% purity) challenged with anti-IgE","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods on highly purified cell population, replicated across 12–13 experiments","pmids":["7543533"],"is_preprint":false},{"year":1996,"finding":"Schistosome egg-induced IL-5 is required to recruit eosinophils to the peritoneum, and these recruited eosinophils are themselves a direct source of early IL-4 production (shown by immunocytochemistry), linking IL-5 to downstream IL-4-driven Th2 responses.","method":"Cytokine/mast cell-deficient mouse models (IL-4-/-, IL-5-/-, mast cell-deficient), immunocytochemical detection of IL-4 in eosinophils, cytokine measurement in peritoneal exudate","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple knockout mouse strains plus direct immunocytochemical identification of IL-4-producing eosinophils","pmids":["8920874"],"is_preprint":false},{"year":1997,"finding":"IL-5 inhibits eosinophil apoptosis by upregulating Bcl-2 protein and mRNA expression; antisense oligonucleotide against Bcl-2 blocks the IL-5-mediated eosinophil survival effect, demonstrating that Bcl-2 upregulation is the mechanism of IL-5-promoted eosinophil survival.","method":"In vitro eosinophil culture with rIL-5, apoptosis assay, immunoblot and RT-PCR for Bcl-2, antisense oligonucleotide inhibition","journal":"Clinical and experimental immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mechanistic dissection using antisense knockdown of the proposed effector (Bcl-2), combined with protein and mRNA measurement","pmids":["9010276"],"is_preprint":false},{"year":1997,"finding":"The transcription factor GATA-3 is sufficient to drive IL-5 gene expression in T cells and is required for IL-5 promoter activation; GATA-3 binds with high affinity to an inverted GATA repeat in the IL-5 promoter. By contrast, GATA-3 is not sufficient to drive IL-4 gene expression, revealing differential regulation of these two Th2 cytokine genes.","method":"Ectopic GATA-3 expression in T cells, antisense GATA-3 RNA in Th2 cells, IL-5 promoter-reporter assay, electrophoretic mobility shift assay (EMSA) for GATA-3 binding to IL-5 promoter","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis/reporter assay combined with EMSA and gain/loss-of-function approaches, multiple orthogonal methods","pmids":["9780145"],"is_preprint":false},{"year":1997,"finding":"The cytokine IL-5 possesses a functional nuclear localization signal and co-transports the extracellular domains of both its α and β receptor subunits to the nucleus in vitro via a 'piggy-back' mechanism, suggesting a nuclear signaling role for IL-5.","method":"Baculovirus expression of receptor extracellular domains, fluorescent labeling, in vitro nuclear import assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro nuclear transport assay, single lab, no in-cell functional validation of nuclear IL-5 role","pmids":["9237664"],"is_preprint":false},{"year":1998,"finding":"IL-5 signaling in eosinophils proceeds through two major pathways downstream of its heterodimeric receptor (α-specific, β-common): (1) Lyn → Syk → JAK2 → Ras-MAPK/ERK pathway and (2) JAK-STAT pathway. Lyn, Syk, JAK2, and SHP-2 promote eosinophil survival; Raf-1 (but not Lyn or JAK2) is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5-stimulated B cell function but not eosinophil function.","method":"Immunoprecipitation, kinase assays, pharmacological inhibitors, functional assays (survival, degranulation, adhesion) in human eosinophils","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pathway components dissected with orthogonal biochemical and functional assays, consistent with independent literature","pmids":["9730944"],"is_preprint":false},{"year":1998,"finding":"High-affinity binding of IL-5 to its receptor induces receptor oligomerization, tyrosine kinase activation (primarily JAK2), receptor phosphorylation, and recruitment of SH2/PTB domain-containing adaptor proteins; a phosphotyrosine-independent signaling motif in the cytoplasmic domain of βc mediates survival and differentiation signals.","method":"Receptor reconstitution, mutagenesis of βc, phosphorylation and co-immunoprecipitation assays","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor mutagenesis and co-IP data across the receptor family, single review integrating original data","pmids":["9766809"],"is_preprint":false},{"year":1999,"finding":"IL-5 increases expression of FLAP (5-lipoxygenase-activating protein) in human blood eosinophils (by ~51% at protein level) and translocates 5-lipoxygenase to the nucleus, thereby enhancing cysteinyl-leukotriene C4 synthesis ~4-fold; these effects are blocked by cycloheximide and actinomycin D, indicating new gene expression is required.","method":"Immunostaining for FLAP and 5-LO, immunoblotting, leukotriene C4 synthesis assay, immunofluorescence microscopy, cycloheximide/actinomycin D inhibition","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunostaining, Western, functional lipid mediator assay, inhibitor experiments) in a single rigorous study","pmids":["10384149"],"is_preprint":false},{"year":1999,"finding":"p38 MAP kinase selectively regulates IL-5 synthesis in human Th cells: the p38 inhibitor SB203580 dose-dependently suppresses IL-5 production without affecting IL-2, IL-4, or IFN-γ production or T-cell proliferation.","method":"p38 MAP kinase inhibitor (SB203580) treatment of allergen-specific human Th clones, cytokine ELISA, [3H]thymidine proliferation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective pharmacological inhibition with parallel cytokine measurements, single lab","pmids":["10528175"],"is_preprint":false},{"year":1999,"finding":"IL-2 specifically induces IL-5 mRNA expression (peaking at 24 h) in PBMC from onchocerciasis patients; this induction is abolished by neutralizing anti-IL-2 antibodies. IL-2 does not induce IL-4, IFN-γ, IL-10, or GM-CSF mRNA, and the primary source of IL-5 mRNA is CD4+ T cells.","method":"RT-PCR for cytokine mRNA, anti-IL-2 neutralizing antibody blocking, CD4+ T cell identification","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody blockade plus cytokine-specific mRNA analysis, single lab","pmids":["8099937"],"is_preprint":false},{"year":2000,"finding":"IL-5 upregulates cysteinyl leukotriene 1 receptor (CysLT1R) mRNA (2–15-fold within 2–4 h) and protein on eosinophil-differentiated HL-60 cells, resulting in enhanced LTD4-induced Ca2+ mobilization and chemotaxis; this effect requires eosinophil differentiation and is absent in undifferentiated HL-60 cells.","method":"Northern/RT-PCR for CysLT1R mRNA, flow cytometry for surface protein, Ca2+ flux assay, chemotaxis assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts with differentiation-state controls, single lab","pmids":["11046055"],"is_preprint":false},{"year":2000,"finding":"Activated mutants of the βc (common β) subunit reveal that IL-5R activation can occur via multiple states differing in receptor stoichiometry; JAK2 activation is the initiating signaling event, and βc dimerization serves as a receptor trigger; β subunit tyrosine phosphorylation generates proliferative and survival signals.","method":"Site-directed mutagenesis, activated βc mutant isolation, functional assays in cell lines and primary cells, receptor phosphorylation analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of receptor with multiple functional assays, single lab","pmids":["10720688"],"is_preprint":false},{"year":2001,"finding":"IL-5 is necessary and sufficient for eosinophil trafficking to the esophagus: IL-5-transgenic mice (T cell- or enterocyte-driven) show markedly elevated esophageal eosinophils, pharmacological IL-5 administration induces esophageal eosinophilia, and IL-5-deficient mice are resistant to allergen-induced eosinophilic esophagitis. IL-5-driven esophageal eosinophilia is eotaxin-dependent in part.","method":"IL-5-transgenic mice, IL-5 knockout mice, miniosmotic pump IL-5 delivery, allergen challenge model, genetic cross with eotaxin-deficient mice, histological quantification","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function (transgenic), loss-of-function (KO), and pharmacological approaches combined in one study","pmids":["11859139"],"is_preprint":false},{"year":2001,"finding":"IL-5 deficiency leads to decreased titers of atheroprotective T15/EO6 natural IgM (anti-phosphorylcholine) and accelerated atherosclerosis; IL-5 provides non-cognate stimulation to innate B-1 cells to secrete T15/EO6 IgM, linking adaptive Th2 IL-5 production to innate B-1 cell antibody output.","method":"Bone marrow transplant model, IL-5-deficient mice, antibody titer measurement, atherosclerosis quantification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — bone marrow transplant plus genetic deficiency model with clear functional readout (IgM titers, atherosclerotic lesion area)","pmids":["15286809"],"is_preprint":false},{"year":2001,"finding":"IL-5 overexpression mediates ectopic bone formation in the spleen (ossification) and perturbs skeletal bone metabolism through mobilization of marrow-derived osteogenic progenitors; this effect is transferable by adoptive engraftment of transgenic marrow.","method":"IL-5-transgenic mouse (NJ.1638), histology (osteoid/osteocyte characterization), morphometric assessment, bone marrow adoptive transfer to wild-type recipients","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic gain-of-function with adoptive transfer confirmation, single lab","pmids":["11306598"],"is_preprint":false},{"year":2002,"finding":"The IL-5 receptor α (IL-5Rα) is selectively expressed on bronchial smooth muscle (but not on saphenous vein or jejunum smooth muscle), and IL-5 directly primes human bronchus for hyperresponsiveness to acetylcholine (17–20-fold reduction in EC50) independent of eosinophils; this effect is blocked by anti-IL-5 and anti-IL-5Rα antibodies.","method":"Human bronchus organ bath contractility assay, RT-PCR for IL-5Rα and CCR3, antibody neutralization","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct functional assay on isolated human tissue with receptor expression profiling and antibody blockade confirming specificity","pmids":["11897983"],"is_preprint":false},{"year":2002,"finding":"IL-13-induced airway eosinophilia (throughout the lung parenchyma) is IL-5-dependent: IL-5 KO mice show markedly attenuated lung eosinophilia in response to intranasal IL-13, while IL-5-transgenic mice show greatly amplified eosinophilia. IL-13-induced mucus production is not affected by IL-5 or eotaxin, dissociating mucus secretion mechanistically from eosinophilia.","method":"IL-5 KO mice, IL-5 transgenic mice, eotaxin KO mice, double-deficient mice, recombinant murine IL-13 intranasal delivery, histological quantification of BAL and tissue eosinophils, mucus staining","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO, transgenic, double KO) with orthogonal readouts","pmids":["11590387"],"is_preprint":false},{"year":2002,"finding":"Pulmonary IL-5 expression induces airway mucus production through a CD4+ T cell-dependent, IL-4Rα-mediated pathway; mucus accumulation in IL-5-transgenic mice is abolished by deficiency of CD4+ cells, αβ TCR+ cells, or anti-IL-4Rα treatment, even though eosinophilia and IL-5 levels remain elevated.","method":"IL-5-transgenic mice crossed with CD4-/- and αβTCR-/- knockout mice, anti-IL-4Rα antagonist treatment, mucus quantification","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological approaches dissecting the IL-5 → CD4+ T cell → IL-4Rα → mucus pathway","pmids":["11943672"],"is_preprint":false},{"year":2002,"finding":"Bcl6 binds to a specific sequence (IL5BS) in the 3'-UTR of the murine and human IL-5 genes and acts as a transcriptional repressor; Bcl6-deficient mice overproduce IL-5 specifically among Th2 cytokines, and mutation of the IL5BS abolishes Bcl6-mediated repression in reporter assays.","method":"Gel retardation assay, chromatin immunoprecipitation (ChIP), reporter gene assays with wild-type and mutant IL5BS, Bcl6-deficient and lck-Bcl6-transgenic mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct DNA-binding evidence (EMSA + ChIP), functional promoter mutagenesis, and in vivo genetic validation","pmids":["12097386"],"is_preprint":false},{"year":2006,"finding":"IL-5 augments liver fibrosis in Schistosoma mansoni infection by regulating IL-13 activity: IL-5 KO mice show >40% reduction in hepatic fibrosis and loss of alternative macrophage activation markers (arginase-1, Fizz-1, YM-1) despite similar IL-13 production. Granuloma eosinophils are themselves a significant source of IL-13, revealing both direct (eosinophil IL-13 production) and indirect (Th2 polarization) roles for IL-5 in fibrosis.","method":"IL-5 knockout mice, S. mansoni infection model, histomorphometric fibrosis quantification, gene expression analysis (arginase-1, Fizz-1, YM-1), cytokine measurement","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with mechanistic gene expression profiling revealing specific IL-13-regulatory pathway","pmids":["16495517"],"is_preprint":false},{"year":2007,"finding":"In IL-5-transgenic mice with greatly expanded circulating eosinophils, MCA-induced fibrosarcoma incidence and growth are significantly attenuated; histology shows massive eosinophil infiltration in tumors; anti-IL-5Rα and anti-asialo GM1 antibodies reverse the protective effect, implicating eosinophils (and NK cells) as effectors; eosinophils directly kill MCA-induced fibrosarcoma cells in vitro.","method":"IL-5-transgenic mice, eotaxin-1-deficient mice, eosinophil-deficient strains (IL-5/CCL11-/-, DeltadblGATA), carcinogen-induced tumor model, antibody depletion, in vitro cytotoxicity assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models, antibody depletion, and in vitro cytotoxicity providing convergent mechanistic evidence","pmids":["17371978"],"is_preprint":false},{"year":2007,"finding":"JAK kinase activity is required for ubiquitination of the βc cytoplasmic domain (at lysine residues K566 and K603) and subsequent proteasomal degradation but only partially required for IL-5R internalization; ubiquitination begins at the plasma membrane, increases after internalization, and proteasomal degradation of βc occurs after internalization, followed by terminal lysosomal degradation.","method":"Flow cytometry, biochemical ubiquitination assays, site-directed mutagenesis of K566/K603, JAK inhibitor treatment, immunoprecipitation","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis identifying specific ubiquitination sites combined with biochemical and flow cytometric methods","pmids":["17227823"],"is_preprint":false},{"year":2008,"finding":"IL-5Rs internalize via two distinct endocytic pathways — clathrin-dependent and lipid raft-dependent; activated (tyrosine-phosphorylated, ubiquitinated, proteasome-targeted) IL-5Rs partition selectively to the clathrin/non-raft fraction; optimal IL-5-induced signaling requires receptor internalization, as blocking either endocytic pathway inhibits co-immunoprecipitation of key signaling molecules with IL-5R.","method":"Deconvolution microscopy, co-immunoprecipitation, endocytosis inhibitors, transferrin (clathrin) and cholera toxin-B (lipid raft) markers, biochemical fractionation in TF1 cells and human eosinophils","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (microscopy, co-IP, biochemical fractionation) with inhibitor validation, single lab","pmids":["18511572"],"is_preprint":false},{"year":2010,"finding":"SATB1 directly represses IL-5 transcription during early human Th2 cell differentiation by binding to the IL-5 promoter; SATB1 knockdown increases IL-5 expression, and this up-regulation is partly counteracted by GATA-3 knockdown, indicating a competitive mechanism between SATB1 and GATA-3 at the IL-5 promoter.","method":"SATB1 ChIP on IL-5 promoter, RNAi knockdown of SATB1 and GATA3, IL-5 mRNA measurement in differentiating human Th2 cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct promoter occupancy (ChIP) combined with functional RNAi knockdown of both competing transcription factors","pmids":["20522714"],"is_preprint":false},{"year":2011,"finding":"IL-5(+) Th2 cells (a minority ~20% subpopulation of Th2 cells) show greater GATA-3 and H3K4me3 binding to the IL-5 promoter, while IL-5(-) Th2 cells show greater H3K27me3 at the IL-5 promoter, demonstrating that hierarchical, epigenetic regulation governs IL-5 gene accessibility within Th2 subsets.","method":"Intracellular cytokine staining, ChIP for GATA-3/H3K4me3/H3K27me3 at IL-5 promoter, in vitro serial Th2 differentiation, surface marker phenotyping","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP analysis combined with functional cell sorting and in vitro differentiation showing epigenetic mechanism","pmids":["21849680"],"is_preprint":false},{"year":2011,"finding":"IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct-2; IL-5 signals through JAK-STAT, Btk, and Ras/Raf-ERK pathways in B cells and eosinophils to maintain survival and function.","method":"Transcription factor binding studies, signaling pathway analyses (cited as part of a comprehensive mechanistic review integrating original research data)","journal":"Proceedings of the Japan Academy. Series B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review summarizing original mechanistic experiments on IL-5Rα transcriptional regulation and signaling, but abstract-level evidence is lower confidence","pmids":["21986312"],"is_preprint":false},{"year":2011,"finding":"PARP-1 is required for STAT-6 protein integrity downstream of IL-4R activation; in PARP-1-/- mice, STAT-6 is degraded by calpain (not proteasomes), leading to reduced GATA-3 and consequently reduced IL-5 mRNA and protein in allergen-stimulated conditions. PARP-1 enzymatic activity (not just its presence) is required for STAT-6 stability.","method":"PARP-1 knockout mice, allergen-induced asthma model, IL-5 ELISA, STAT-6 and GATA-3 immunoblotting, calpain/proteasome inhibitor experiments, ChIP for GATA-3 at IL-5 promoter, IL-5 replenishment experiments","journal":"Allergy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic pathway dissection using pharmacological inhibitors and ChIP in a single rigorous study","pmids":["21276008"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the βc ectodomain reveals an intertwined homodimer with four fibronectin type-III-like domains per chain; domain 1 of one subunit swaps β-strands with domain 3 of the other. Site-directed mutagenesis identifies the interface between domains 1 and 4 as the functional signaling epitope required for IL-5/IL-3/GM-CSF signaling.","method":"X-ray crystallography, site-directed mutagenesis","journal":"Vitamins and hormones","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with functional mutagenesis","pmids":["17027509"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of IL-5 bound to the extracellular domain of IL-5Rα reveals a wrench-like architecture in which IL-5 contacts all three fibronectin III-like domains of IL-5Rα. Mutagenesis confirms the wrench is likely pre-formed. Structural analysis demonstrates that homodimeric IL-5 can bind only one receptor molecule at a time due to steric constraints, even though two equivalent receptor-binding sites exist.","method":"X-ray crystallography of IL-5/IL-5Rα ectodomain complex, site-directed mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation providing atomic-level mechanism of receptor recognition","pmids":["22153509"],"is_preprint":false},{"year":2015,"finding":"LZTFL1 (upregulated by all-trans retinoic acid in CD4+ T cells) localizes to the plasma membrane, redistributes to the immunological synapse during T cell activation, and promotes IL-5 production: LZTFL1 knockdown reduces IL-5 levels, while overexpression enhances TCR-mediated NFAT signaling.","method":"Live-cell imaging, siRNA knockdown, overexpression, NFAT reporter assay, IL-5 ELISA in CD4+ T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with imaging and signaling reporter, single lab","pmids":["26700766"],"is_preprint":false},{"year":2016,"finding":"IL-33 supports eosinophil homeostasis upstream of IL-5: IL-33 drives expansion of IL-5Rα-expressing eosinophil precursor cells in vitro (an effect not produced by IL-5 itself), and the IL-33-induced expansion of mature eosinophils in vivo requires IL-5 (blocked by anti-IL-5 antibody). ST2 deficiency reduces the hypereosinophilia seen in IL-5-transgenic mice despite similar IL-5 levels, positioning IL-33 upstream of IL-5 in eosinophil lineage commitment.","method":"IL-33-/- and ST2-/- mice, IL-5 transgenic mice crossed with ST2-/-, IL-5-neutralizing antibody, in vitro bone marrow culture with IL-33 or IL-5, flow cytometry for precursor populations","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models with neutralizing antibody and in vitro mechanistic experiments","pmids":["27683753"],"is_preprint":false},{"year":2019,"finding":"IL-5, but not IL-13 or IL-4, directly induces hyperresponsiveness of human small airway smooth muscle: IL-5 does not induce hyperresponsiveness in isolated human small bronchi or human airway smooth muscle cells, in contrast to IL-13 and IL-4 (negative finding mechanistically informative for IL-5).","method":"Ex vivo human small bronchi organ bath assay, human airway smooth muscle cell culture, contractility measurements, Ca2+ mobilization, RNA sequencing","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional assay on isolated human tissue; IL-5 negative result is rigorous and informative","pmids":["31805312"],"is_preprint":false},{"year":2019,"finding":"Human airway bronchial epithelial cells (HBEC) express a functional IL-5 receptor that triggers intracellular signaling and changes gene expression upon IL-5 stimulation, identifying a direct non-eosinophil target for IL-5 in the airway.","method":"IL-5 receptor expression on HBEC, signaling assays, gene expression analysis","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — receptor expression with functional signaling shown, single lab, abstract lacks full methodological detail","pmids":["32246831"],"is_preprint":false},{"year":2019,"finding":"Neutrophils infiltrating mouse and human (pediatric asthma BAL) inflamed lungs express IL-5Rα (CD125), and the IL-5 receptor on neutrophils is capable of signal transduction; IL-5-mediated protection from influenza A virus infection is independent of eosinophils in mice, suggesting neutrophils as an alternative cellular target.","method":"Flow cytometry for IL-5Rα on neutrophils from mouse lungs and human BAL, IL-5R signal transduction assay, IL-5-deficient mice, influenza infection model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — flow cytometry combined with functional signaling assay and genetic KO model, single lab","pmids":["31415658"],"is_preprint":false},{"year":2019,"finding":"Mast cell-derived IL-5 is important for maintaining the population of IL-10-producing regulatory B cells (IL-10+ Breg) in peripheral lymphoid tissues, which in turn suppress IL-13-producing ILC2s in oxazolone-induced contact hypersensitivity; this reveals a MC → IL-5 → Breg → ILC2 immunoregulatory axis.","method":"Mast cell-specific models, IL-5 neutralization, flow cytometric characterization of Breg and ILC2 populations, contact hypersensitivity model in mice","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with cytokine neutralization and cell population analysis, single lab","pmids":["31328158"],"is_preprint":false},{"year":2020,"finding":"IL-5 stimulates migration and activation of pancreatic tumor cells through STAT5 signaling via IL-5Rα expressed on tumor cells; IL-5Rα expression increases during pancreatic tumor progression in mice and is detectable in human pancreatic ductal adenocarcinoma (7/7 cases by IHC).","method":"Mouse pancreatic tumor progression models (Akt1Myr/KRasG12D), immunohistochemistry, STAT5 signaling analysis, cell migration assay","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional migration assay with signaling data and IHC in mouse and human samples, single lab","pmids":["32552827"],"is_preprint":false},{"year":2022,"finding":"The E3 ubiquitin ligases MARCH2 and MARCH3 associate with IL-5Rα, mediate K27-linked polyubiquitination of IL-5Rα at K379 (MARCH2) and K383 (MARCH3), and target it for lysosomal degradation; double knockout of MARCH2/3 enhances IL-5-induced signaling, increases eosinophil numbers in bone marrow and blood, and aggravates OVA-induced eosinophilic airway inflammation.","method":"Co-immunoprecipitation, ubiquitination assays with K27-linkage specificity, site-directed mutagenesis (K379/K383), MARCH2/3 knockout mice (single and double), OVA airway inflammation model, IL-5 neutralization in vivo","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ubiquitination assay with site-specific mutagenesis, genetic KO validation in vivo, and mechanistic rescue by IL-5 neutralization","pmids":["35982175"],"is_preprint":false},{"year":2024,"finding":"IL-5 promotes eosinophil-lineage expansion specifically through transit amplification of committed progenitors, but deletion or neutralization of IL-5 does not compromise eosinophil maturation per se; IL-5Rα reporter mice and single-cell proteomics/transcriptomics define the precise stage of IL-5 action in eosinophilopoiesis.","method":"Single-cell proteomics, single-cell transcriptomics, transgenic IL-5Rα reporter mice, IL-5 deletion/neutralization, cell-surface immunophenotyping across eosinophil maturation stages","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-cell multi-omic methods combined with genetic models precisely positioning IL-5 action in the eosinophil developmental continuum","pmids":["38776917"],"is_preprint":false}],"current_model":"IL-5 is a homodimeric glycoprotein cytokine that signals through a heterodimeric receptor (IL-5Rα/βc), activating JAK2, Lyn, Syk, the Ras-MAPK/ERK, and JAK-STAT pathways to promote eosinophil-lineage transit amplification, survival (via Bcl-2 upregulation), degranulation (via Raf-1), leukotriene synthesis (via FLAP upregulation and 5-LO nuclear translocation), and CysLT1R expression, while also driving B-1 cell IgA/IgM production and direct bronchial hyperresponsiveness; its transcription is activated by GATA-3 (at an inverted GATA repeat in the IL-5 promoter), enhanced by LZTFL1/NFAT and the PARP-1→STAT-6→GATA-3 axis, and repressed by SATB1 and Bcl6 (via an IL5BS silencer in the 3'-UTR), with receptor downregulation controlled by JAK2-dependent K27-linked ubiquitination at K566/K603 of βc (by the proteasome pathway) and at K379/K383 of IL-5Rα by MARCH2/3 E3 ligases (lysosomal pathway)."},"narrative":{"mechanistic_narrative":"IL-5 is a homodimeric glycoprotein cytokine that orchestrates the eosinophil lineage and Th2 immune effector responses [PMID:3284812, PMID:38776917]. It signals through a heterodimeric receptor composed of an IL-5-specific α chain required for ligand binding and a common β chain (βc) shared with the IL-3 and GM-CSF receptors that confers high-affinity binding and signal transduction [PMID:1613263, PMID:7950399]; crystallographic analysis shows IL-5 contacts all three fibronectin-III domains of IL-5Rα in a pre-formed wrench-like architecture and, despite its symmetry, binds only one receptor at a time, while the intertwined βc homodimer presents a domain 1–4 interface as the functional signaling epitope [PMID:17027509, PMID:22153509]. Receptor engagement activates JAK2 as the initiating event, with JAK2 coupling to STAT1, and operates through parallel Lyn→Syk→JAK2→Ras-MAPK/ERK and JAK-STAT arms; these enzymes partition functional outputs, with Lyn/Syk/JAK2/SHP-2 supporting survival and Raf-1 driving degranulation and adhesion [PMID:7602114, PMID:9730944]. In eosinophils, IL-5 promotes survival by upregulating Bcl-2 [PMID:9010276], enhances cysteinyl-leukotriene synthesis by inducing FLAP and translocating 5-lipoxygenase to the nucleus [PMID:10384149], and induces CysLT1 receptor expression to amplify leukotriene responsiveness [PMID:11046055]. At the developmental level, IL-5 acts on committed progenitors via transit amplification rather than maturation, downstream of IL-33-driven precursor expansion [PMID:27683753, PMID:38776917]. Beyond eosinophils, IL-5 drives terminal B-cell differentiation into Ig-secreting cells and sustains B-1 cell IgM output [PMID:3284812, PMID:15286809], and directly primes human bronchial smooth muscle for hyperresponsiveness through IL-5Rα [PMID:11897983]. IL-5 transcription is governed by GATA-3 binding an inverted GATA repeat in the promoter [PMID:9780145], opposed by the repressors SATB1 (promoter) and Bcl6 (binding the IL5BS element in the 3'-UTR) [PMID:12097386, PMID:20522714], and the PARP-1→STAT-6→GATA-3 axis sustains its expression [PMID:21276008]. Receptor levels are controlled by JAK2-dependent K27-linked ubiquitination of βc at K566/K603 targeting proteasomal degradation and by MARCH2/3-mediated ubiquitination of IL-5Rα at K379/K383 targeting lysosomal degradation [PMID:17227823, PMID:35982175].","teleology":[{"year":1988,"claim":"Established the molecular identity of IL-5 as a homodimeric glycoprotein and its first effector function as a B-cell terminal differentiation factor, distinguishing differentiation from proliferation.","evidence":"cDNA cloning, recombinant expression, and B-cell differentiation/proliferation assays with purified cell subsets","pmids":["3284812","3258891","3348775"],"confidence":"High","gaps":["Receptor identity and signaling mechanism not yet defined","Eosinophil role not yet addressed in these studies"]},{"year":1991,"claim":"Defined the IL-5 receptor on eosinophils as a single high-affinity specific binding entity, opening the question of its subunit composition.","evidence":"Radiolabeled IL-5 binding, Scatchard analysis, and affinity cross-linking on human eosinophils","pmids":["2015632"],"confidence":"High","gaps":["Subunit architecture and shared components unresolved","Downstream signaling not characterized"]},{"year":1992,"claim":"Resolved the receptor as an α/βc heterodimer sharing a common β subunit with IL-3R and GM-CSFR, explaining functional overlap and high-affinity binding requirements.","evidence":"Receptor subunit cloning, high-affinity reconstitution, and signaling assays across the cytokine receptor family","pmids":["1613263","7950399"],"confidence":"High","gaps":["Identity of the receptor-associated kinases not yet known","Mechanism of receptor triggering unresolved"]},{"year":1995,"claim":"Identified JAK2-STAT1 as a proximal signaling axis and revealed mast cells as a non-T-cell cellular source of IL-5.","evidence":"Co-IP of JAK2 with βc, kinase and phosphorylation assays, EMSA in eosinophils; RT-PCR/ISH/ELISA in FcεRI-activated lung mast cells","pmids":["7602114","7543533"],"confidence":"High","gaps":["Full branching of downstream pathways not yet mapped","Functional contribution of mast cell IL-5 in vivo undefined here"]},{"year":1997,"claim":"Dissected the effector mechanism for eosinophil survival (Bcl-2 upregulation) and established GATA-3 as the master transcriptional activator binding the IL-5 promoter.","evidence":"Antisense Bcl-2 knockdown in eosinophils; GATA-3 gain/loss-of-function with promoter-reporter and EMSA in T cells","pmids":["9010276","9780145"],"confidence":"High","gaps":["Repressive transcriptional control not yet identified","Connection between survival signaling and apoptosis machinery beyond Bcl-2 incomplete"]},{"year":1998,"claim":"Mapped IL-5 signaling into two functional arms and assigned distinct kinases to survival versus degranulation/adhesion outputs.","evidence":"Immunoprecipitation, kinase assays, pharmacological inhibitors, and functional eosinophil assays; receptor mutagenesis of βc","pmids":["9730944","9766809"],"confidence":"High","gaps":["Precise adaptor recruitment events partly inferred","βc phosphotyrosine-independent motif effectors not fully defined"]},{"year":1999,"claim":"Connected IL-5 signaling to eosinophil lipid-mediator output via FLAP induction, 5-LO nuclear translocation, and selective p38-dependent IL-5 synthesis control in Th cells.","evidence":"Immunostaining, immunoblot, LTC4 assays with transcription/translation inhibitors; p38 inhibitor SB203580 with cytokine ELISA in Th clones","pmids":["10384149","10528175","8099937"],"confidence":"High","gaps":["Whether p38 acts at the IL-5 promoter directly not shown","Physiological relevance of IL-2-induced IL-5 outside parasitic infection unclear"]},{"year":2000,"claim":"Linked IL-5 to amplified leukotriene responsiveness through CysLT1R upregulation and refined the receptor-triggering model around βc dimerization and JAK2 as the initiating event.","evidence":"CysLT1R mRNA/protein, Ca2+ flux and chemotaxis in differentiated HL-60; activated βc mutants and phosphorylation analysis","pmids":["11046055","10720688"],"confidence":"Medium","gaps":["CysLT1R findings in HL-60 model not confirmed in primary eosinophils here","Stoichiometry of active receptor states inferred from mutants"]},{"year":2002,"claim":"Established IL-5 as both necessary and sufficient for tissue eosinophilia and identified direct, eosinophil-independent action on bronchial smooth muscle, plus dual transcriptional repressors.","evidence":"IL-5 transgenic/KO and IL-13 challenge models; human bronchus contractility assays with antibody blockade; Bcl6 EMSA/ChIP/reporter and KO mice","pmids":["11859139","11897983","11590387","11943672","12097386"],"confidence":"High","gaps":["Mechanism of direct smooth muscle priming not molecularly defined","Mucus production shown to be IL-5-independent at effector level"]},{"year":2007,"claim":"Defined IL-5 receptor turnover via JAK-dependent βc ubiquitination at K566/K603 and proteasomal degradation, integrating signaling with receptor downregulation.","evidence":"Site-directed mutagenesis of βc lysines, ubiquitination assays, JAK inhibition, and flow cytometry","pmids":["17227823"],"confidence":"High","gaps":["E3 ligase for βc ubiquitination not identified","Relationship between proteasomal and lysosomal arms incomplete"]},{"year":2008,"claim":"Showed receptor internalization through clathrin- versus raft-dependent routes is required for optimal signaling, coupling endocytic sorting to signal output.","evidence":"Deconvolution microscopy, co-IP, endocytosis inhibitors and fractionation in TF1 cells and eosinophils","pmids":["18511572"],"confidence":"High","gaps":["Specific signaling complexes assembled on internalized receptor not fully enumerated"]},{"year":2011,"claim":"Provided atomic-resolution receptor recognition mechanisms and elaborated the transcriptional and epigenetic logic of IL-5 expression including the PARP-1→STAT-6→GATA-3 axis and competitive SATB1/GATA-3 control.","evidence":"X-ray structures of βc and IL-5/IL-5Rα with mutagenesis; ChIP for GATA-3/H3K4me3/H3K27me3; PARP-1 KO with calpain/proteasome inhibitors and ChIP","pmids":["17027509","22153509","20522714","21849680","21276008","21986312"],"confidence":"High","gaps":["Full assembly of the active higher-order receptor complex from these isolated structures not resolved","How epigenetic marks are set in IL-5+ versus IL-5- Th2 subsets mechanistically unclear"]},{"year":2016,"claim":"Positioned IL-33 upstream of IL-5 in eosinophil lineage commitment and identified LZTFL1/NFAT as a positive modulator of IL-5 production in T cells.","evidence":"IL-33/ST2 KO and IL-5 transgenic crosses with anti-IL-5 neutralization and bone marrow culture; LZTFL1 imaging, knockdown/overexpression, NFAT reporter","pmids":["27683753","26700766"],"confidence":"High","gaps":["Molecular link between IL-33 sensing and IL-5 transcription not defined","LZTFL1 mechanism single-lab"]},{"year":2019,"claim":"Broadened the IL-5 target-cell repertoire to bronchial epithelium and neutrophils while clarifying that direct small-airway smooth muscle hyperresponsiveness is IL-5-independent in human tissue.","evidence":"Human small bronchi/ASM organ bath and RNA-seq; IL-5R expression and signaling on HBEC and on neutrophils with influenza KO model","pmids":["31805312","32246831","31415658"],"confidence":"Medium","gaps":["Apparent discordance with earlier bronchial hyperresponsiveness finding unresolved within the corpus","Functional consequence of epithelial/neutrophil IL-5R signaling not fully established"]},{"year":2022,"claim":"Identified MARCH2/3 as the E3 ligases driving K27-linked ubiquitination of IL-5Rα at K379/K383 and lysosomal degradation, completing the receptor-downregulation picture and demonstrating its in vivo control of eosinophilic inflammation.","evidence":"Co-IP, K27-linkage-specific ubiquitination, site-directed mutagenesis, MARCH2/3 KO mice, and OVA airway inflammation with IL-5 neutralization","pmids":["35982175"],"confidence":"High","gaps":["Signals regulating MARCH2/3 recruitment to IL-5Rα unknown","Interplay between βc proteasomal and IL-5Rα lysosomal degradation arms not jointly dissected"]},{"year":2024,"claim":"Precisely placed IL-5 action at the transit-amplification stage of committed eosinophil progenitors rather than at maturation, refining its developmental role.","evidence":"Single-cell proteomics/transcriptomics, IL-5Rα reporter mice, and IL-5 deletion/neutralization across maturation stages","pmids":["38776917"],"confidence":"High","gaps":["Molecular effectors distinguishing amplification from maturation not defined","Whether this developmental logic extends to human eosinophilopoiesis untested here"]},{"year":null,"claim":"It remains unresolved how the diverse non-eosinophil IL-5 targets (epithelium, neutrophils, smooth muscle, B/Breg cells, tumor cells) and the apparently divergent human small-airway findings integrate into a unified mechanistic model of IL-5 action.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconciliation of direct bronchial smooth muscle effects across human tissue studies","Signaling outputs in non-eosinophil targets incompletely characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,5,35]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,12,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,23,44]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[37,44]}],"complexes":["IL-5 receptor (IL-5Rα/βc heterodimer)"],"partners":["IL5RA","CSF2RB","JAK2","STAT1","LYN","SYK","MARCH2","MARCH3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05113","full_name":"Interleukin-5","aliases":["B-cell differentiation factor I","Eosinophil differentiation factor","T-cell replacing factor","TRF"],"length_aa":134,"mass_kda":15.2,"function":"Homodimeric cytokine expressed predominantly by T-lymphocytes and NK cells that plays an important role in the survival, differentiation, and chemotaxis of eosinophils (PubMed:2653458, PubMed:9010276). Also acts on activated and resting B-cells to induce immunoglobulin production, growth, and differentiation (By similarity). Mechanistically, exerts its biological effects through a receptor composed of IL5RA subunit and the cytokine receptor common subunit beta/CSF2RB (PubMed:1495999, PubMed:22528658). Binding to the receptor leads to activation of various kinases including LYN, SYK and JAK2 and thereby propagates signals through the RAS-MAPK and JAK-STAT5 pathways respectively (PubMed:7613138)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P05113/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL5","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL5","total_profiled":1310},"omim":[{"mim_id":"620874","title":"ADHESION G PROTEIN-COUPLED RECEPTOR F5; ADGRF5","url":"https://www.omim.org/entry/620874"},{"mim_id":"619630","title":"IMMUNODEFICIENCY 88; IMD88","url":"https://www.omim.org/entry/619630"},{"mim_id":"618999","title":"AUTOINFLAMMATION, IMMUNE DYSREGULATION, AND EOSINOPHILIA; AIIDE","url":"https://www.omim.org/entry/618999"},{"mim_id":"617144","title":"MICRO RNA 4435-2 HOST GENE, NONCODING; MIR4435-2HG","url":"https://www.omim.org/entry/617144"},{"mim_id":"616005","title":"IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36","url":"https://www.omim.org/entry/616005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":4.8}],"url":"https://www.proteinatlas.org/search/IL5"},"hgnc":{"alias_symbol":["IL-5","EDF","TRF"],"prev_symbol":[]},"alphafold":{"accession":"P05113","domains":[{"cath_id":"1.20.1250.10","chopping":"25-105","consensus_level":"high","plddt":95.3873,"start":25,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05113","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05113-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05113-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL5","jax_strain_url":"https://www.jax.org/strain/search?query=IL5"},"sequence":{"accession":"P05113","fasta_url":"https://rest.uniprot.org/uniprotkb/P05113.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05113/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05113"}},"corpus_meta":[{"pmid":"11754819","id":"PMC_11754819","title":"IL-25 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cloning, recombinant protein expression, functional B-cell differentiation assays, immunoprecipitation with specific mAbs\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — molecular cloning combined with direct functional reconstitution and antibody neutralization, foundational characterization replicated across multiple assays in the same study\",\n      \"pmids\": [\"3284812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"IL-5 acts specifically on mIgA-positive Peyer's patch B cells to promote terminal differentiation into IgA-secreting cells without driving cell proliferation, establishing that IL-5 is a differentiation (not proliferation) factor acting downstream of IgA isotype switching.\",\n      \"method\": \"Cell sorting of mIgA+ vs mIgA- B cells, rIL-5 stimulation, ELISPOT assay, [3H]thymidine incorporation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution with purified cell subsets and multiple orthogonal readouts (IgA secretion, ELISPOT, proliferation assay)\",\n      \"pmids\": [\"3258891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Recombinant EDF (IL-5) expressed in CHO cells retains its dimeric structure and biological activity identical to natural EDF, confirming the homodimeric architecture is sufficient for function.\",\n      \"method\": \"Recombinant expression in CHO DHFR- cells, methotrexate selection, biochemical characterization of secreted protein\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution in CHO cells with activity confirmation, single study\",\n      \"pmids\": [\"3348775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Human eosinophils express a single class of high-affinity IL-5 receptor (Kd ~170–330 pM; ~260–380 sites/cell) with a molecular mass of 55–60 kDa identified by affinity cross-linking; IL-5 binding is inhibited by excess unlabeled IL-5 or anti-IL-5 mAb but not by other cytokines, demonstrating receptor specificity.\",\n      \"method\": \"Radiolabeled IL-5 binding assay, Scatchard analysis, affinity cross-linking, competition binding\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct receptor characterization with multiple biophysical and biochemical methods in a single focused study\",\n      \"pmids\": [\"2015632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The high-affinity receptors for IL-5, IL-3, and GM-CSF are heterodimers composed of a cytokine-specific α subunit and a shared common β subunit; the β subunit is required both for high-affinity ligand binding and for signal transduction, including tyrosine phosphorylation and Ras protein activation. In humans, a single common β subunit is shared among all three receptors.\",\n      \"method\": \"Molecular cloning of receptor subunits, reconstitution of high-affinity receptors, signal transduction assays\",\n      \"journal\": \"International journal of cell cloning\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — receptor reconstitution and signaling assays, replicated across multiple cytokine receptor systems\",\n      \"pmids\": [\"1613263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"IL-5 is a homodimeric glycoprotein that signals through a heterodimeric receptor comprising a unique IL-5-specific α chain (required for ligand binding) and a common β chain shared with IL-3R and GM-CSFR (required for high-affinity binding and signaling).\",\n      \"method\": \"Biochemical characterization, receptor reconstitution studies\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive receptor characterization review citing reconstitution data, consistent with independent studies\",\n      \"pmids\": [\"7950399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IL-5 activates the JAK2–STAT1 signaling pathway in human eosinophils: JAK2 is tyrosine-phosphorylated within 1–3 min of IL-5 stimulation, physically associates (co-precipitates) with the β subunit of the IL-5 receptor, and STAT1 (p91) is subsequently tyrosine-phosphorylated and translocates to the nucleus to bind the gamma-activating sequence.\",\n      \"method\": \"Immunoprecipitation, immunoblotting for tyrosine phosphorylation, JAK2 autophosphorylation assay, co-IP of JAK2 with IL-5Rβ, EMSA with anti-STAT1 supershift\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods (co-IP, kinase assay, EMSA) in a single rigorous study\",\n      \"pmids\": [\"7602114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IgE-dependent activation of human lung mast cells (via FcεRI crosslinking) induces IL-5 mRNA expression within 2 h (persisting 48–72 h) and release of immunoreactive IL-5 protein (~731 pg/10^6 cells over 48 h), identifying mast cells as a non-T-cell source of IL-5.\",\n      \"method\": \"RT-PCR, in situ hybridization, double in situ hybridization-immunocytochemistry, ELISA; purified mast cells (>93% purity) challenged with anti-IgE\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods on highly purified cell population, replicated across 12–13 experiments\",\n      \"pmids\": [\"7543533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Schistosome egg-induced IL-5 is required to recruit eosinophils to the peritoneum, and these recruited eosinophils are themselves a direct source of early IL-4 production (shown by immunocytochemistry), linking IL-5 to downstream IL-4-driven Th2 responses.\",\n      \"method\": \"Cytokine/mast cell-deficient mouse models (IL-4-/-, IL-5-/-, mast cell-deficient), immunocytochemical detection of IL-4 in eosinophils, cytokine measurement in peritoneal exudate\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple knockout mouse strains plus direct immunocytochemical identification of IL-4-producing eosinophils\",\n      \"pmids\": [\"8920874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"IL-5 inhibits eosinophil apoptosis by upregulating Bcl-2 protein and mRNA expression; antisense oligonucleotide against Bcl-2 blocks the IL-5-mediated eosinophil survival effect, demonstrating that Bcl-2 upregulation is the mechanism of IL-5-promoted eosinophil survival.\",\n      \"method\": \"In vitro eosinophil culture with rIL-5, apoptosis assay, immunoblot and RT-PCR for Bcl-2, antisense oligonucleotide inhibition\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mechanistic dissection using antisense knockdown of the proposed effector (Bcl-2), combined with protein and mRNA measurement\",\n      \"pmids\": [\"9010276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The transcription factor GATA-3 is sufficient to drive IL-5 gene expression in T cells and is required for IL-5 promoter activation; GATA-3 binds with high affinity to an inverted GATA repeat in the IL-5 promoter. By contrast, GATA-3 is not sufficient to drive IL-4 gene expression, revealing differential regulation of these two Th2 cytokine genes.\",\n      \"method\": \"Ectopic GATA-3 expression in T cells, antisense GATA-3 RNA in Th2 cells, IL-5 promoter-reporter assay, electrophoretic mobility shift assay (EMSA) for GATA-3 binding to IL-5 promoter\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis/reporter assay combined with EMSA and gain/loss-of-function approaches, multiple orthogonal methods\",\n      \"pmids\": [\"9780145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The cytokine IL-5 possesses a functional nuclear localization signal and co-transports the extracellular domains of both its α and β receptor subunits to the nucleus in vitro via a 'piggy-back' mechanism, suggesting a nuclear signaling role for IL-5.\",\n      \"method\": \"Baculovirus expression of receptor extracellular domains, fluorescent labeling, in vitro nuclear import assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro nuclear transport assay, single lab, no in-cell functional validation of nuclear IL-5 role\",\n      \"pmids\": [\"9237664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IL-5 signaling in eosinophils proceeds through two major pathways downstream of its heterodimeric receptor (α-specific, β-common): (1) Lyn → Syk → JAK2 → Ras-MAPK/ERK pathway and (2) JAK-STAT pathway. Lyn, Syk, JAK2, and SHP-2 promote eosinophil survival; Raf-1 (but not Lyn or JAK2) is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5-stimulated B cell function but not eosinophil function.\",\n      \"method\": \"Immunoprecipitation, kinase assays, pharmacological inhibitors, functional assays (survival, degranulation, adhesion) in human eosinophils\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pathway components dissected with orthogonal biochemical and functional assays, consistent with independent literature\",\n      \"pmids\": [\"9730944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"High-affinity binding of IL-5 to its receptor induces receptor oligomerization, tyrosine kinase activation (primarily JAK2), receptor phosphorylation, and recruitment of SH2/PTB domain-containing adaptor proteins; a phosphotyrosine-independent signaling motif in the cytoplasmic domain of βc mediates survival and differentiation signals.\",\n      \"method\": \"Receptor reconstitution, mutagenesis of βc, phosphorylation and co-immunoprecipitation assays\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor mutagenesis and co-IP data across the receptor family, single review integrating original data\",\n      \"pmids\": [\"9766809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL-5 increases expression of FLAP (5-lipoxygenase-activating protein) in human blood eosinophils (by ~51% at protein level) and translocates 5-lipoxygenase to the nucleus, thereby enhancing cysteinyl-leukotriene C4 synthesis ~4-fold; these effects are blocked by cycloheximide and actinomycin D, indicating new gene expression is required.\",\n      \"method\": \"Immunostaining for FLAP and 5-LO, immunoblotting, leukotriene C4 synthesis assay, immunofluorescence microscopy, cycloheximide/actinomycin D inhibition\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunostaining, Western, functional lipid mediator assay, inhibitor experiments) in a single rigorous study\",\n      \"pmids\": [\"10384149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p38 MAP kinase selectively regulates IL-5 synthesis in human Th cells: the p38 inhibitor SB203580 dose-dependently suppresses IL-5 production without affecting IL-2, IL-4, or IFN-γ production or T-cell proliferation.\",\n      \"method\": \"p38 MAP kinase inhibitor (SB203580) treatment of allergen-specific human Th clones, cytokine ELISA, [3H]thymidine proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective pharmacological inhibition with parallel cytokine measurements, single lab\",\n      \"pmids\": [\"10528175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL-2 specifically induces IL-5 mRNA expression (peaking at 24 h) in PBMC from onchocerciasis patients; this induction is abolished by neutralizing anti-IL-2 antibodies. IL-2 does not induce IL-4, IFN-γ, IL-10, or GM-CSF mRNA, and the primary source of IL-5 mRNA is CD4+ T cells.\",\n      \"method\": \"RT-PCR for cytokine mRNA, anti-IL-2 neutralizing antibody blocking, CD4+ T cell identification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody blockade plus cytokine-specific mRNA analysis, single lab\",\n      \"pmids\": [\"8099937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-5 upregulates cysteinyl leukotriene 1 receptor (CysLT1R) mRNA (2–15-fold within 2–4 h) and protein on eosinophil-differentiated HL-60 cells, resulting in enhanced LTD4-induced Ca2+ mobilization and chemotaxis; this effect requires eosinophil differentiation and is absent in undifferentiated HL-60 cells.\",\n      \"method\": \"Northern/RT-PCR for CysLT1R mRNA, flow cytometry for surface protein, Ca2+ flux assay, chemotaxis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts with differentiation-state controls, single lab\",\n      \"pmids\": [\"11046055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Activated mutants of the βc (common β) subunit reveal that IL-5R activation can occur via multiple states differing in receptor stoichiometry; JAK2 activation is the initiating signaling event, and βc dimerization serves as a receptor trigger; β subunit tyrosine phosphorylation generates proliferative and survival signals.\",\n      \"method\": \"Site-directed mutagenesis, activated βc mutant isolation, functional assays in cell lines and primary cells, receptor phosphorylation analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of receptor with multiple functional assays, single lab\",\n      \"pmids\": [\"10720688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-5 is necessary and sufficient for eosinophil trafficking to the esophagus: IL-5-transgenic mice (T cell- or enterocyte-driven) show markedly elevated esophageal eosinophils, pharmacological IL-5 administration induces esophageal eosinophilia, and IL-5-deficient mice are resistant to allergen-induced eosinophilic esophagitis. IL-5-driven esophageal eosinophilia is eotaxin-dependent in part.\",\n      \"method\": \"IL-5-transgenic mice, IL-5 knockout mice, miniosmotic pump IL-5 delivery, allergen challenge model, genetic cross with eotaxin-deficient mice, histological quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function (transgenic), loss-of-function (KO), and pharmacological approaches combined in one study\",\n      \"pmids\": [\"11859139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-5 deficiency leads to decreased titers of atheroprotective T15/EO6 natural IgM (anti-phosphorylcholine) and accelerated atherosclerosis; IL-5 provides non-cognate stimulation to innate B-1 cells to secrete T15/EO6 IgM, linking adaptive Th2 IL-5 production to innate B-1 cell antibody output.\",\n      \"method\": \"Bone marrow transplant model, IL-5-deficient mice, antibody titer measurement, atherosclerosis quantification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bone marrow transplant plus genetic deficiency model with clear functional readout (IgM titers, atherosclerotic lesion area)\",\n      \"pmids\": [\"15286809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-5 overexpression mediates ectopic bone formation in the spleen (ossification) and perturbs skeletal bone metabolism through mobilization of marrow-derived osteogenic progenitors; this effect is transferable by adoptive engraftment of transgenic marrow.\",\n      \"method\": \"IL-5-transgenic mouse (NJ.1638), histology (osteoid/osteocyte characterization), morphometric assessment, bone marrow adoptive transfer to wild-type recipients\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain-of-function with adoptive transfer confirmation, single lab\",\n      \"pmids\": [\"11306598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The IL-5 receptor α (IL-5Rα) is selectively expressed on bronchial smooth muscle (but not on saphenous vein or jejunum smooth muscle), and IL-5 directly primes human bronchus for hyperresponsiveness to acetylcholine (17–20-fold reduction in EC50) independent of eosinophils; this effect is blocked by anti-IL-5 and anti-IL-5Rα antibodies.\",\n      \"method\": \"Human bronchus organ bath contractility assay, RT-PCR for IL-5Rα and CCR3, antibody neutralization\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay on isolated human tissue with receptor expression profiling and antibody blockade confirming specificity\",\n      \"pmids\": [\"11897983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-13-induced airway eosinophilia (throughout the lung parenchyma) is IL-5-dependent: IL-5 KO mice show markedly attenuated lung eosinophilia in response to intranasal IL-13, while IL-5-transgenic mice show greatly amplified eosinophilia. IL-13-induced mucus production is not affected by IL-5 or eotaxin, dissociating mucus secretion mechanistically from eosinophilia.\",\n      \"method\": \"IL-5 KO mice, IL-5 transgenic mice, eotaxin KO mice, double-deficient mice, recombinant murine IL-13 intranasal delivery, histological quantification of BAL and tissue eosinophils, mucus staining\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO, transgenic, double KO) with orthogonal readouts\",\n      \"pmids\": [\"11590387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Pulmonary IL-5 expression induces airway mucus production through a CD4+ T cell-dependent, IL-4Rα-mediated pathway; mucus accumulation in IL-5-transgenic mice is abolished by deficiency of CD4+ cells, αβ TCR+ cells, or anti-IL-4Rα treatment, even though eosinophilia and IL-5 levels remain elevated.\",\n      \"method\": \"IL-5-transgenic mice crossed with CD4-/- and αβTCR-/- knockout mice, anti-IL-4Rα antagonist treatment, mucus quantification\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological approaches dissecting the IL-5 → CD4+ T cell → IL-4Rα → mucus pathway\",\n      \"pmids\": [\"11943672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Bcl6 binds to a specific sequence (IL5BS) in the 3'-UTR of the murine and human IL-5 genes and acts as a transcriptional repressor; Bcl6-deficient mice overproduce IL-5 specifically among Th2 cytokines, and mutation of the IL5BS abolishes Bcl6-mediated repression in reporter assays.\",\n      \"method\": \"Gel retardation assay, chromatin immunoprecipitation (ChIP), reporter gene assays with wild-type and mutant IL5BS, Bcl6-deficient and lck-Bcl6-transgenic mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct DNA-binding evidence (EMSA + ChIP), functional promoter mutagenesis, and in vivo genetic validation\",\n      \"pmids\": [\"12097386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-5 augments liver fibrosis in Schistosoma mansoni infection by regulating IL-13 activity: IL-5 KO mice show >40% reduction in hepatic fibrosis and loss of alternative macrophage activation markers (arginase-1, Fizz-1, YM-1) despite similar IL-13 production. Granuloma eosinophils are themselves a significant source of IL-13, revealing both direct (eosinophil IL-13 production) and indirect (Th2 polarization) roles for IL-5 in fibrosis.\",\n      \"method\": \"IL-5 knockout mice, S. mansoni infection model, histomorphometric fibrosis quantification, gene expression analysis (arginase-1, Fizz-1, YM-1), cytokine measurement\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with mechanistic gene expression profiling revealing specific IL-13-regulatory pathway\",\n      \"pmids\": [\"16495517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In IL-5-transgenic mice with greatly expanded circulating eosinophils, MCA-induced fibrosarcoma incidence and growth are significantly attenuated; histology shows massive eosinophil infiltration in tumors; anti-IL-5Rα and anti-asialo GM1 antibodies reverse the protective effect, implicating eosinophils (and NK cells) as effectors; eosinophils directly kill MCA-induced fibrosarcoma cells in vitro.\",\n      \"method\": \"IL-5-transgenic mice, eotaxin-1-deficient mice, eosinophil-deficient strains (IL-5/CCL11-/-, DeltadblGATA), carcinogen-induced tumor model, antibody depletion, in vitro cytotoxicity assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models, antibody depletion, and in vitro cytotoxicity providing convergent mechanistic evidence\",\n      \"pmids\": [\"17371978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAK kinase activity is required for ubiquitination of the βc cytoplasmic domain (at lysine residues K566 and K603) and subsequent proteasomal degradation but only partially required for IL-5R internalization; ubiquitination begins at the plasma membrane, increases after internalization, and proteasomal degradation of βc occurs after internalization, followed by terminal lysosomal degradation.\",\n      \"method\": \"Flow cytometry, biochemical ubiquitination assays, site-directed mutagenesis of K566/K603, JAK inhibitor treatment, immunoprecipitation\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis identifying specific ubiquitination sites combined with biochemical and flow cytometric methods\",\n      \"pmids\": [\"17227823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-5Rs internalize via two distinct endocytic pathways — clathrin-dependent and lipid raft-dependent; activated (tyrosine-phosphorylated, ubiquitinated, proteasome-targeted) IL-5Rs partition selectively to the clathrin/non-raft fraction; optimal IL-5-induced signaling requires receptor internalization, as blocking either endocytic pathway inhibits co-immunoprecipitation of key signaling molecules with IL-5R.\",\n      \"method\": \"Deconvolution microscopy, co-immunoprecipitation, endocytosis inhibitors, transferrin (clathrin) and cholera toxin-B (lipid raft) markers, biochemical fractionation in TF1 cells and human eosinophils\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (microscopy, co-IP, biochemical fractionation) with inhibitor validation, single lab\",\n      \"pmids\": [\"18511572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SATB1 directly represses IL-5 transcription during early human Th2 cell differentiation by binding to the IL-5 promoter; SATB1 knockdown increases IL-5 expression, and this up-regulation is partly counteracted by GATA-3 knockdown, indicating a competitive mechanism between SATB1 and GATA-3 at the IL-5 promoter.\",\n      \"method\": \"SATB1 ChIP on IL-5 promoter, RNAi knockdown of SATB1 and GATA3, IL-5 mRNA measurement in differentiating human Th2 cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct promoter occupancy (ChIP) combined with functional RNAi knockdown of both competing transcription factors\",\n      \"pmids\": [\"20522714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-5(+) Th2 cells (a minority ~20% subpopulation of Th2 cells) show greater GATA-3 and H3K4me3 binding to the IL-5 promoter, while IL-5(-) Th2 cells show greater H3K27me3 at the IL-5 promoter, demonstrating that hierarchical, epigenetic regulation governs IL-5 gene accessibility within Th2 subsets.\",\n      \"method\": \"Intracellular cytokine staining, ChIP for GATA-3/H3K4me3/H3K27me3 at IL-5 promoter, in vitro serial Th2 differentiation, surface marker phenotyping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP analysis combined with functional cell sorting and in vitro differentiation showing epigenetic mechanism\",\n      \"pmids\": [\"21849680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-5Rα expression in activated B cells is regulated by a complex of transcription factors including E12, E47, Sp1, c/EBPβ, and Oct-2; IL-5 signals through JAK-STAT, Btk, and Ras/Raf-ERK pathways in B cells and eosinophils to maintain survival and function.\",\n      \"method\": \"Transcription factor binding studies, signaling pathway analyses (cited as part of a comprehensive mechanistic review integrating original research data)\",\n      \"journal\": \"Proceedings of the Japan Academy. Series B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review summarizing original mechanistic experiments on IL-5Rα transcriptional regulation and signaling, but abstract-level evidence is lower confidence\",\n      \"pmids\": [\"21986312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PARP-1 is required for STAT-6 protein integrity downstream of IL-4R activation; in PARP-1-/- mice, STAT-6 is degraded by calpain (not proteasomes), leading to reduced GATA-3 and consequently reduced IL-5 mRNA and protein in allergen-stimulated conditions. PARP-1 enzymatic activity (not just its presence) is required for STAT-6 stability.\",\n      \"method\": \"PARP-1 knockout mice, allergen-induced asthma model, IL-5 ELISA, STAT-6 and GATA-3 immunoblotting, calpain/proteasome inhibitor experiments, ChIP for GATA-3 at IL-5 promoter, IL-5 replenishment experiments\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic pathway dissection using pharmacological inhibitors and ChIP in a single rigorous study\",\n      \"pmids\": [\"21276008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the βc ectodomain reveals an intertwined homodimer with four fibronectin type-III-like domains per chain; domain 1 of one subunit swaps β-strands with domain 3 of the other. Site-directed mutagenesis identifies the interface between domains 1 and 4 as the functional signaling epitope required for IL-5/IL-3/GM-CSF signaling.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis\",\n      \"journal\": \"Vitamins and hormones\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with functional mutagenesis\",\n      \"pmids\": [\"17027509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of IL-5 bound to the extracellular domain of IL-5Rα reveals a wrench-like architecture in which IL-5 contacts all three fibronectin III-like domains of IL-5Rα. Mutagenesis confirms the wrench is likely pre-formed. Structural analysis demonstrates that homodimeric IL-5 can bind only one receptor molecule at a time due to steric constraints, even though two equivalent receptor-binding sites exist.\",\n      \"method\": \"X-ray crystallography of IL-5/IL-5Rα ectodomain complex, site-directed mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation providing atomic-level mechanism of receptor recognition\",\n      \"pmids\": [\"22153509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LZTFL1 (upregulated by all-trans retinoic acid in CD4+ T cells) localizes to the plasma membrane, redistributes to the immunological synapse during T cell activation, and promotes IL-5 production: LZTFL1 knockdown reduces IL-5 levels, while overexpression enhances TCR-mediated NFAT signaling.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, overexpression, NFAT reporter assay, IL-5 ELISA in CD4+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with imaging and signaling reporter, single lab\",\n      \"pmids\": [\"26700766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-33 supports eosinophil homeostasis upstream of IL-5: IL-33 drives expansion of IL-5Rα-expressing eosinophil precursor cells in vitro (an effect not produced by IL-5 itself), and the IL-33-induced expansion of mature eosinophils in vivo requires IL-5 (blocked by anti-IL-5 antibody). ST2 deficiency reduces the hypereosinophilia seen in IL-5-transgenic mice despite similar IL-5 levels, positioning IL-33 upstream of IL-5 in eosinophil lineage commitment.\",\n      \"method\": \"IL-33-/- and ST2-/- mice, IL-5 transgenic mice crossed with ST2-/-, IL-5-neutralizing antibody, in vitro bone marrow culture with IL-33 or IL-5, flow cytometry for precursor populations\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models with neutralizing antibody and in vitro mechanistic experiments\",\n      \"pmids\": [\"27683753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-5, but not IL-13 or IL-4, directly induces hyperresponsiveness of human small airway smooth muscle: IL-5 does not induce hyperresponsiveness in isolated human small bronchi or human airway smooth muscle cells, in contrast to IL-13 and IL-4 (negative finding mechanistically informative for IL-5).\",\n      \"method\": \"Ex vivo human small bronchi organ bath assay, human airway smooth muscle cell culture, contractility measurements, Ca2+ mobilization, RNA sequencing\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional assay on isolated human tissue; IL-5 negative result is rigorous and informative\",\n      \"pmids\": [\"31805312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human airway bronchial epithelial cells (HBEC) express a functional IL-5 receptor that triggers intracellular signaling and changes gene expression upon IL-5 stimulation, identifying a direct non-eosinophil target for IL-5 in the airway.\",\n      \"method\": \"IL-5 receptor expression on HBEC, signaling assays, gene expression analysis\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — receptor expression with functional signaling shown, single lab, abstract lacks full methodological detail\",\n      \"pmids\": [\"32246831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neutrophils infiltrating mouse and human (pediatric asthma BAL) inflamed lungs express IL-5Rα (CD125), and the IL-5 receptor on neutrophils is capable of signal transduction; IL-5-mediated protection from influenza A virus infection is independent of eosinophils in mice, suggesting neutrophils as an alternative cellular target.\",\n      \"method\": \"Flow cytometry for IL-5Rα on neutrophils from mouse lungs and human BAL, IL-5R signal transduction assay, IL-5-deficient mice, influenza infection model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — flow cytometry combined with functional signaling assay and genetic KO model, single lab\",\n      \"pmids\": [\"31415658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mast cell-derived IL-5 is important for maintaining the population of IL-10-producing regulatory B cells (IL-10+ Breg) in peripheral lymphoid tissues, which in turn suppress IL-13-producing ILC2s in oxazolone-induced contact hypersensitivity; this reveals a MC → IL-5 → Breg → ILC2 immunoregulatory axis.\",\n      \"method\": \"Mast cell-specific models, IL-5 neutralization, flow cytometric characterization of Breg and ILC2 populations, contact hypersensitivity model in mice\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with cytokine neutralization and cell population analysis, single lab\",\n      \"pmids\": [\"31328158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-5 stimulates migration and activation of pancreatic tumor cells through STAT5 signaling via IL-5Rα expressed on tumor cells; IL-5Rα expression increases during pancreatic tumor progression in mice and is detectable in human pancreatic ductal adenocarcinoma (7/7 cases by IHC).\",\n      \"method\": \"Mouse pancreatic tumor progression models (Akt1Myr/KRasG12D), immunohistochemistry, STAT5 signaling analysis, cell migration assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional migration assay with signaling data and IHC in mouse and human samples, single lab\",\n      \"pmids\": [\"32552827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The E3 ubiquitin ligases MARCH2 and MARCH3 associate with IL-5Rα, mediate K27-linked polyubiquitination of IL-5Rα at K379 (MARCH2) and K383 (MARCH3), and target it for lysosomal degradation; double knockout of MARCH2/3 enhances IL-5-induced signaling, increases eosinophil numbers in bone marrow and blood, and aggravates OVA-induced eosinophilic airway inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K27-linkage specificity, site-directed mutagenesis (K379/K383), MARCH2/3 knockout mice (single and double), OVA airway inflammation model, IL-5 neutralization in vivo\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ubiquitination assay with site-specific mutagenesis, genetic KO validation in vivo, and mechanistic rescue by IL-5 neutralization\",\n      \"pmids\": [\"35982175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-5 promotes eosinophil-lineage expansion specifically through transit amplification of committed progenitors, but deletion or neutralization of IL-5 does not compromise eosinophil maturation per se; IL-5Rα reporter mice and single-cell proteomics/transcriptomics define the precise stage of IL-5 action in eosinophilopoiesis.\",\n      \"method\": \"Single-cell proteomics, single-cell transcriptomics, transgenic IL-5Rα reporter mice, IL-5 deletion/neutralization, cell-surface immunophenotyping across eosinophil maturation stages\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-cell multi-omic methods combined with genetic models precisely positioning IL-5 action in the eosinophil developmental continuum\",\n      \"pmids\": [\"38776917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-5 is a homodimeric glycoprotein cytokine that signals through a heterodimeric receptor (IL-5Rα/βc), activating JAK2, Lyn, Syk, the Ras-MAPK/ERK, and JAK-STAT pathways to promote eosinophil-lineage transit amplification, survival (via Bcl-2 upregulation), degranulation (via Raf-1), leukotriene synthesis (via FLAP upregulation and 5-LO nuclear translocation), and CysLT1R expression, while also driving B-1 cell IgA/IgM production and direct bronchial hyperresponsiveness; its transcription is activated by GATA-3 (at an inverted GATA repeat in the IL-5 promoter), enhanced by LZTFL1/NFAT and the PARP-1→STAT-6→GATA-3 axis, and repressed by SATB1 and Bcl6 (via an IL5BS silencer in the 3'-UTR), with receptor downregulation controlled by JAK2-dependent K27-linked ubiquitination at K566/K603 of βc (by the proteasome pathway) and at K379/K383 of IL-5Rα by MARCH2/3 E3 ligases (lysosomal pathway).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-5 is a homodimeric glycoprotein cytokine that orchestrates the eosinophil lineage and Th2 immune effector responses [#0, #44]. It signals through a heterodimeric receptor composed of an IL-5-specific α chain required for ligand binding and a common β chain (βc) shared with the IL-3 and GM-CSF receptors that confers high-affinity binding and signal transduction [#4, #5]; crystallographic analysis shows IL-5 contacts all three fibronectin-III domains of IL-5Rα in a pre-formed wrench-like architecture and, despite its symmetry, binds only one receptor at a time, while the intertwined βc homodimer presents a domain 1–4 interface as the functional signaling epitope [#34, #35]. Receptor engagement activates JAK2 as the initiating event, with JAK2 coupling to STAT1, and operates through parallel Lyn→Syk→JAK2→Ras-MAPK/ERK and JAK-STAT arms; these enzymes partition functional outputs, with Lyn/Syk/JAK2/SHP-2 supporting survival and Raf-1 driving degranulation and adhesion [#6, #12]. In eosinophils, IL-5 promotes survival by upregulating Bcl-2 [#9], enhances cysteinyl-leukotriene synthesis by inducing FLAP and translocating 5-lipoxygenase to the nucleus [#14], and induces CysLT1 receptor expression to amplify leukotriene responsiveness [#17]. At the developmental level, IL-5 acts on committed progenitors via transit amplification rather than maturation, downstream of IL-33-driven precursor expansion [#37, #44]. Beyond eosinophils, IL-5 drives terminal B-cell differentiation into Ig-secreting cells and sustains B-1 cell IgM output [#0, #20], and directly primes human bronchial smooth muscle for hyperresponsiveness through IL-5Rα [#22]. IL-5 transcription is governed by GATA-3 binding an inverted GATA repeat in the promoter [#10], opposed by the repressors SATB1 (promoter) and Bcl6 (binding the IL5BS element in the 3'-UTR) [#25, #30], and the PARP-1→STAT-6→GATA-3 axis sustains its expression [#33]. Receptor levels are controlled by JAK2-dependent K27-linked ubiquitination of βc at K566/K603 targeting proteasomal degradation and by MARCH2/3-mediated ubiquitination of IL-5Rα at K379/K383 targeting lysosomal degradation [#28, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established the molecular identity of IL-5 as a homodimeric glycoprotein and its first effector function as a B-cell terminal differentiation factor, distinguishing differentiation from proliferation.\",\n      \"evidence\": \"cDNA cloning, recombinant expression, and B-cell differentiation/proliferation assays with purified cell subsets\",\n      \"pmids\": [\"3284812\", \"3258891\", \"3348775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity and signaling mechanism not yet defined\", \"Eosinophil role not yet addressed in these studies\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defined the IL-5 receptor on eosinophils as a single high-affinity specific binding entity, opening the question of its subunit composition.\",\n      \"evidence\": \"Radiolabeled IL-5 binding, Scatchard analysis, and affinity cross-linking on human eosinophils\",\n      \"pmids\": [\"2015632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit architecture and shared components unresolved\", \"Downstream signaling not characterized\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Resolved the receptor as an α/βc heterodimer sharing a common β subunit with IL-3R and GM-CSFR, explaining functional overlap and high-affinity binding requirements.\",\n      \"evidence\": \"Receptor subunit cloning, high-affinity reconstitution, and signaling assays across the cytokine receptor family\",\n      \"pmids\": [\"1613263\", \"7950399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the receptor-associated kinases not yet known\", \"Mechanism of receptor triggering unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified JAK2-STAT1 as a proximal signaling axis and revealed mast cells as a non-T-cell cellular source of IL-5.\",\n      \"evidence\": \"Co-IP of JAK2 with βc, kinase and phosphorylation assays, EMSA in eosinophils; RT-PCR/ISH/ELISA in FcεRI-activated lung mast cells\",\n      \"pmids\": [\"7602114\", \"7543533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full branching of downstream pathways not yet mapped\", \"Functional contribution of mast cell IL-5 in vivo undefined here\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Dissected the effector mechanism for eosinophil survival (Bcl-2 upregulation) and established GATA-3 as the master transcriptional activator binding the IL-5 promoter.\",\n      \"evidence\": \"Antisense Bcl-2 knockdown in eosinophils; GATA-3 gain/loss-of-function with promoter-reporter and EMSA in T cells\",\n      \"pmids\": [\"9010276\", \"9780145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repressive transcriptional control not yet identified\", \"Connection between survival signaling and apoptosis machinery beyond Bcl-2 incomplete\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped IL-5 signaling into two functional arms and assigned distinct kinases to survival versus degranulation/adhesion outputs.\",\n      \"evidence\": \"Immunoprecipitation, kinase assays, pharmacological inhibitors, and functional eosinophil assays; receptor mutagenesis of βc\",\n      \"pmids\": [\"9730944\", \"9766809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise adaptor recruitment events partly inferred\", \"βc phosphotyrosine-independent motif effectors not fully defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected IL-5 signaling to eosinophil lipid-mediator output via FLAP induction, 5-LO nuclear translocation, and selective p38-dependent IL-5 synthesis control in Th cells.\",\n      \"evidence\": \"Immunostaining, immunoblot, LTC4 assays with transcription/translation inhibitors; p38 inhibitor SB203580 with cytokine ELISA in Th clones\",\n      \"pmids\": [\"10384149\", \"10528175\", \"8099937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p38 acts at the IL-5 promoter directly not shown\", \"Physiological relevance of IL-2-induced IL-5 outside parasitic infection unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked IL-5 to amplified leukotriene responsiveness through CysLT1R upregulation and refined the receptor-triggering model around βc dimerization and JAK2 as the initiating event.\",\n      \"evidence\": \"CysLT1R mRNA/protein, Ca2+ flux and chemotaxis in differentiated HL-60; activated βc mutants and phosphorylation analysis\",\n      \"pmids\": [\"11046055\", \"10720688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CysLT1R findings in HL-60 model not confirmed in primary eosinophils here\", \"Stoichiometry of active receptor states inferred from mutants\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established IL-5 as both necessary and sufficient for tissue eosinophilia and identified direct, eosinophil-independent action on bronchial smooth muscle, plus dual transcriptional repressors.\",\n      \"evidence\": \"IL-5 transgenic/KO and IL-13 challenge models; human bronchus contractility assays with antibody blockade; Bcl6 EMSA/ChIP/reporter and KO mice\",\n      \"pmids\": [\"11859139\", \"11897983\", \"11590387\", \"11943672\", \"12097386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of direct smooth muscle priming not molecularly defined\", \"Mucus production shown to be IL-5-independent at effector level\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined IL-5 receptor turnover via JAK-dependent βc ubiquitination at K566/K603 and proteasomal degradation, integrating signaling with receptor downregulation.\",\n      \"evidence\": \"Site-directed mutagenesis of βc lysines, ubiquitination assays, JAK inhibition, and flow cytometry\",\n      \"pmids\": [\"17227823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for βc ubiquitination not identified\", \"Relationship between proteasomal and lysosomal arms incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed receptor internalization through clathrin- versus raft-dependent routes is required for optimal signaling, coupling endocytic sorting to signal output.\",\n      \"evidence\": \"Deconvolution microscopy, co-IP, endocytosis inhibitors and fractionation in TF1 cells and eosinophils\",\n      \"pmids\": [\"18511572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific signaling complexes assembled on internalized receptor not fully enumerated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided atomic-resolution receptor recognition mechanisms and elaborated the transcriptional and epigenetic logic of IL-5 expression including the PARP-1→STAT-6→GATA-3 axis and competitive SATB1/GATA-3 control.\",\n      \"evidence\": \"X-ray structures of βc and IL-5/IL-5Rα with mutagenesis; ChIP for GATA-3/H3K4me3/H3K27me3; PARP-1 KO with calpain/proteasome inhibitors and ChIP\",\n      \"pmids\": [\"17027509\", \"22153509\", \"20522714\", \"21849680\", \"21276008\", \"21986312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full assembly of the active higher-order receptor complex from these isolated structures not resolved\", \"How epigenetic marks are set in IL-5+ versus IL-5- Th2 subsets mechanistically unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned IL-33 upstream of IL-5 in eosinophil lineage commitment and identified LZTFL1/NFAT as a positive modulator of IL-5 production in T cells.\",\n      \"evidence\": \"IL-33/ST2 KO and IL-5 transgenic crosses with anti-IL-5 neutralization and bone marrow culture; LZTFL1 imaging, knockdown/overexpression, NFAT reporter\",\n      \"pmids\": [\"27683753\", \"26700766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between IL-33 sensing and IL-5 transcription not defined\", \"LZTFL1 mechanism single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the IL-5 target-cell repertoire to bronchial epithelium and neutrophils while clarifying that direct small-airway smooth muscle hyperresponsiveness is IL-5-independent in human tissue.\",\n      \"evidence\": \"Human small bronchi/ASM organ bath and RNA-seq; IL-5R expression and signaling on HBEC and on neutrophils with influenza KO model\",\n      \"pmids\": [\"31805312\", \"32246831\", \"31415658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent discordance with earlier bronchial hyperresponsiveness finding unresolved within the corpus\", \"Functional consequence of epithelial/neutrophil IL-5R signaling not fully established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified MARCH2/3 as the E3 ligases driving K27-linked ubiquitination of IL-5Rα at K379/K383 and lysosomal degradation, completing the receptor-downregulation picture and demonstrating its in vivo control of eosinophilic inflammation.\",\n      \"evidence\": \"Co-IP, K27-linkage-specific ubiquitination, site-directed mutagenesis, MARCH2/3 KO mice, and OVA airway inflammation with IL-5 neutralization\",\n      \"pmids\": [\"35982175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals regulating MARCH2/3 recruitment to IL-5Rα unknown\", \"Interplay between βc proteasomal and IL-5Rα lysosomal degradation arms not jointly dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Precisely placed IL-5 action at the transit-amplification stage of committed eosinophil progenitors rather than at maturation, refining its developmental role.\",\n      \"evidence\": \"Single-cell proteomics/transcriptomics, IL-5Rα reporter mice, and IL-5 deletion/neutralization across maturation stages\",\n      \"pmids\": [\"38776917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors distinguishing amplification from maturation not defined\", \"Whether this developmental logic extends to human eosinophilopoiesis untested here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the diverse non-eosinophil IL-5 targets (epithelium, neutrophils, smooth muscle, B/Breg cells, tumor cells) and the apparently divergent human small-airway findings integrate into a unified mechanistic model of IL-5 action.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconciliation of direct bronchial smooth muscle effects across human tissue studies\", \"Signaling outputs in non-eosinophil targets incompletely characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 5, 35]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 12, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 23, 44]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [37, 44]}\n    ],\n    \"complexes\": [\n      \"IL-5 receptor (IL-5Rα/βc heterodimer)\"\n    ],\n    \"partners\": [\n      \"IL5RA\",\n      \"CSF2RB\",\n      \"JAK2\",\n      \"STAT1\",\n      \"LYN\",\n      \"SYK\",\n      \"MARCH2\",\n      \"MARCH3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}