{"gene":"IL25","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-25 (IL-17E) was identified as a ligand for the receptor EVI27/IL-17Rh1 (IL-17BR/IL-17RB). Binding induces NF-κB activation and stimulates production of the proinflammatory chemokine IL-8.","method":"Receptor-ligand binding assay, NF-κB reporter assay, IL-8 production assay in vitro","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct receptor identification with functional NF-κB and cytokine readouts in a focused mechanistic study","pmids":["11058597"],"is_preprint":false},{"year":2001,"finding":"Infusion of IL-25 into mice induced IL-4, IL-5, and IL-13 gene expression and Th2-like responses (elevated serum IgE, IgG1, IgA, blood eosinophilia, lung and gut pathology). IL-25 induced Th2-type cytokine production by MHC class II-high, CD11c-dull, lineage-negative accessory cells.","method":"In vivo cytokine infusion in mice, gene expression analysis, serum immunoglobulin measurement, histology, flow cytometry of responding cell populations","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined cellular targets and downstream cytokine cascade in vivo, replicated across multiple readouts","pmids":["11754819"],"is_preprint":false},{"year":2001,"finding":"Transgenic overexpression of murine IL-17E induces a Th2-biased immune response characterized by eosinophilia, elevated serum IL-13 and IL-5, increased IgE/IgG1, and multi-organ inflammatory pathology. IL-17E also induces G-CSF production in vitro and neutrophilia in vivo.","method":"Transgenic mouse model, serum cytokine and immunoglobulin measurement, histology, in vitro G-CSF assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with multiple orthogonal readouts establishing downstream cytokine cascade","pmids":["11714825"],"is_preprint":false},{"year":2002,"finding":"Intranasal IL-25 induces IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia. IL-25-induced eosinophilia requires IL-5 and IL-13 but not IL-4 or T cells, and requires a gamma-common cytokine receptor-dependent cell population that is B220+, Thy-1+/-, NK1.1-, Ly-6G-, CD4-, CD3-, c-kit-negative.","method":"Adenoviral in vivo delivery, cytokine-deficient and T-cell-deficient mouse models, flow cytometry of responding cell populations, bronchoalveolar lavage analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis using multiple cytokine-deficient mouse lines, defined downstream requirement for IL-5 and IL-13","pmids":["12077275"],"is_preprint":false},{"year":2002,"finding":"Transgenic overexpression of human IL-17E in mice driven by ApoE hepatic promoter causes eosinophilia, B-lymphocyte hyperplasia, elevated serum IL-2, IL-4, IL-5, G-CSF, eotaxin, IFN-γ, and increased IgM, IgG, IgE. In situ hybridization revealed upregulation of the IL-17E receptor IL-17Rh1 (IL-17BR/Evi27) in transgenic tissues.","method":"Transgenic mouse model (ApoE promoter), flow cytometry, serum cytokine/immunoglobulin ELISA, in situ hybridization","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with multiple orthogonal readouts, receptor upregulation confirmed by ISH","pmids":["12239140"],"is_preprint":false},{"year":2006,"finding":"IL-25R (IL-17RB) cross-linking activates NF-κB and MAPK pathways (ERK, JNK, p38). NF-κB activation is mediated specifically by TRAF6 (not TRAF2): dominant-negative TRAF6 blocked IL-25R-mediated NF-κB activation, and NF-κB activation was absent in TRAF6-deficient fibroblasts. TRAF6 co-immunoprecipitates with IL-25R even in the absence of ligand. TRAF6 is required for IL-25R-mediated gene expression of IL-6, TGF-β, G-CSF, and TARC.","method":"Receptor cross-linking assay, dominant-negative transfection, TRAF6-deficient murine embryonic fibroblasts, co-immunoprecipitation, NF-κB reporter assay, gene expression analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, dominant-negative and KO cell systems, multiple orthogonal methods in single focused study","pmids":["16393988"],"is_preprint":false},{"year":2006,"finding":"IL-17E (IL-25) upregulates CCL5, CCL11 (eotaxin), GM-CSF, and CXCL8 mRNA in human primary lung fibroblasts, which constitutively express IL-17BR. IL-17E and TNF-α synergistically induce GM-CSF and CXCL8 production and secretion. TGF-β1 modulates IL-17E-induced responses. IL-17BR mRNA is upregulated by TNF-α and downregulated by TGF-β1.","method":"Primary fibroblast culture, immunofluorescence, Western blot, real-time PCR, ELISA, cytokine stimulation","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor expression confirmed by multiple methods, functional cytokine induction in primary cells, single lab","pmids":["16522458"],"is_preprint":false},{"year":2006,"finding":"TNF-α upregulates IL-17BR expression in airway smooth muscle cells primarily through NF-κB (blocked by IKK2 inhibitor AS-602868). IFN-γ downregulates IL-17BR via the ERK pathway (blocked by MEK inhibitor U0126). IL-17E stimulation of airway smooth muscle cells increases expression of ECM components procollagen-αI and lumican mRNA.","method":"In vitro airway smooth muscle cell culture, pharmacological inhibitors (NF-κB, MEK/ERK), real-time PCR, Western blot, immunohistochemistry of asthmatic biopsies","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors, ECM induction confirmed, single lab","pmids":["16428271"],"is_preprint":false},{"year":2006,"finding":"IL-25-induced airway hyperresponsiveness (AHR) and eosinophilic inflammation are dependent on IL-13, IL-4Rα (IL-4 receptor alpha), and STAT6 signaling, as shown by significantly reduced AHR and mucus production in IL-13−/−, IL-4Rα−/−, and STAT6−/− mice. IL-4 and IL-5/eotaxin1 deficiency also reduced AHR but not mucus hypersecretion. IL-25 can directly act on naïve T cells to promote Th2 responses.","method":"Intratracheal IL-25 instillation in cytokine-deficient mouse strains, plethysmography, histology, BAL analysis","journal":"Clinical and experimental allergy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using multiple cytokine and signaling pathway KO mouse lines with defined phenotypic readouts","pmids":["17177681"],"is_preprint":false},{"year":2007,"finding":"IL-25-deficient mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE), associated with increased IL-23 in the periphery and increased IL-17-, IFN-γ-, and TNF-producing T cells. IL-25 suppresses Th17 responses by inducing IL-13, which directly inhibits IL-23, IL-1β, and IL-6 expression in activated dendritic cells.","method":"IL-25 knockout mice, EAE model, cytokine neutralization (anti-IL-17, anti-IFN-γ), IL-25 treatment in relapsing-remitting and chronic EAE models, dendritic cell stimulation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — IL-25 KO mice plus pharmacological neutralization epistasis, defined mechanism through IL-13→dendritic cell IL-23 suppression","pmids":["17200411"],"is_preprint":false},{"year":2007,"finding":"IL-25 enhances antigen-induced Th2 cytokine production, eosinophil recruitment, and goblet cell hyperplasia in allergic airway inflammation through a Th2 cell-dependent pathway requiring CD4+ T cells and STAT6. Transgenic enforced expression of IL-25 in lung (Clara cell promoter) alone is insufficient to induce inflammation but potentiates allergen-driven responses.","method":"IL-25 transgenic mice (CC10 promoter), CD4+ T cell depletion, STAT6-deficient mice, OVA sensitization model, BAL analysis, histology","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic model plus genetic epistasis (T cell depletion, STAT6 KO), multiple orthogonal readouts","pmids":["16950278"],"is_preprint":false},{"year":2007,"finding":"IL-25 synergistically induces release of Th2 cytokines (IL-4, IL-5, IL-10), IL-6, and chemokines (CXCL9, CXCL10, CCL5) from anti-CD3/CD28 costimulated human memory Th cells. Costimulation upregulates IL-25R surface expression on Th cells. The cytokine release is differentially regulated by JNK, p38 MAPK, and NF-κB pathways.","method":"Human T cell culture with anti-CD3/CD28 costimulation and IL-25, bead-based multiplex cytokine array, flow cytometry for receptor expression, EMSA for NF-κB, Western blot for MAPK, pharmacological inhibitors","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway inhibitors and receptor measurement in primary human cells, single lab","pmids":["17719653"],"is_preprint":false},{"year":2008,"finding":"Commensal bacteria suppress intestinal IL-25 expression by intestinal epithelial cells. In germ-free mice, elevated Th17 cell frequency in the large intestine is associated with reduced IL-25. Commensal-dependent IL-25 limits expansion of Th17 cells by inhibiting macrophage-derived IL-23, defining an IL-25–IL-23–IL-17 axis.","method":"Germ-free mouse model, microbiota colonization, epithelial cell sorting, cytokine quantification, T cell frequency by flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — germ-free model plus mechanistic pathway (IL-25→IL-23 inhibition→Th17 suppression) with multiple cell-type readouts","pmids":["18762568"],"is_preprint":false},{"year":2009,"finding":"Allergen-induced stem cell factor (SCF) promotes IL-25 (IL-17E) production from c-kit+ eosinophils in the lung; bone marrow-derived mast cells did not produce IL-25 in response to SCF. The IL-25R (IL-17RB) was expressed on a CD11b+GR1+Ly6C+/- c-kit- myeloid cell population that is the major source of Th2 cytokines (IL-4) in the lung during chronic allergen challenge.","method":"SCF neutralization in allergen-challenged mice, sorted cell populations for cytokine expression, 4get IL-4 reporter mice, flow cytometry, bone marrow-derived mast cell assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell sorting and reporter mouse to identify producing and responding cell populations, single lab","pmids":["19828636"],"is_preprint":false},{"year":2010,"finding":"IL-25 promotes accumulation of a lineage-negative multipotent progenitor (MPPtype2) cell population (Sca-1+, c-Kitint) in gut-associated lymphoid tissue. MPPtype2 cells exhibit multipotent capacity giving rise to monocyte/macrophage and granulocyte lineages in vitro and in vivo. Adoptive transfer of MPPtype2 cells promotes Th2 cytokine responses and confers protective immunity to helminth infection in IL-25-deficient mice.","method":"Flow cytometry, in vitro and in vivo differentiation assays, adoptive transfer into Il25−/− mice, helminth infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — adoptive transfer reconstitution, in vitro and in vivo multipotency assays, mechanistic placement via IL-25-deficient mice","pmids":["20200520"],"is_preprint":false},{"year":2010,"finding":"IL-25 signals through IL-17RB expressed on in-vitro-generated IL-9-expressing T cells (Th9 cells) to enhance IL-9 expression. Transgenic or retroviral overexpression of IL-17RB in T cells results in IL-25-induced IL-9 production independently of IL-4. In vivo, the IL-25–IL-17RB pathway regulates IL-9 expression in allergic airway inflammation.","method":"In vitro Th9 cell generation, retroviral/transgenic overexpression of IL-17RB, IL-9 cytokine measurement, allergic airway inflammation mouse model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function (retroviral and transgenic overexpression) plus in vivo validation with defined receptor-cytokine coupling","pmids":["20154671"],"is_preprint":false},{"year":2010,"finding":"Protease allergens (papain, Der P1) induce IL-25 and TSLP gene expression in mouse lung epithelial cells via protease activity-dependent activation of ERK and p38 MAPK pathways, but not NF-κB or PI-3 kinase pathways. Deactivation of protease activity abolishes IL-25 induction.","method":"Mouse lung epithelial cell (MLE12) stimulation, protease inactivation controls, pharmacological MAPK inhibitors, real-time PCR, in vivo BAL cytokine measurement","journal":"Journal of Korean medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with protease-inactivated controls in epithelial cells plus in vivo confirmation, single lab","pmids":["20514301"],"is_preprint":false},{"year":2011,"finding":"IL-25 enhances survival of human eosinophils and upregulates ICAM-1 surface expression while suppressing ICAM-3 and L-selectin, increasing eosinophil adhesion to fibronectin. These effects are mediated through p38 MAPK (for L-selectin regulation), JNK (for ICAM-1), and NF-κB/proteasome (for ICAM-3) pathways.","method":"Human eosinophil culture, flow cytometry for adhesion molecules, fibronectin adhesion assay, pharmacological inhibitors (SB203580, SP600125, MG-132), RT-PCR","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of multiple signaling pathways with functional adhesion readout, single lab","pmids":["16792588"],"is_preprint":false},{"year":2011,"finding":"IL-25 activates caspase-mediated apoptosis in IL-25R (IL-17RB)-expressing breast cancer cells through differential receptor expression; nonmalignant mammary epithelial cells with low IL-17RB expression are spared. IL-17RB is expressed at high levels in tumors from patients with poor prognosis but low in nonmalignant breast tissue.","method":"In vitro 3D laminin-rich gel culture, secreted factor screen, caspase activity assays, tumor tissue expression analysis, selective cytotoxicity assays","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor expression correlated with apoptotic sensitivity, caspase activation confirmed, single lab","pmids":["21490275"],"is_preprint":false},{"year":2011,"finding":"IL-25 stimulates angiogenesis in vitro by increasing HUVEC proliferation and microvessel formation in a concentration-dependent manner. HUVECs constitutively express IL-25R (upregulated by TNF-α). IL-25 increases VEGF and VEGF receptor expression. IL-25-induced angiogenesis is blocked by VEGF neutralization, PI3K inhibitor LY294002, and MEK1/2 inhibitor U0126.","method":"In vitro angiogenesis assay (HUVEC), WST-8 proliferation assay, real-time PCR for IL-25R and VEGF, pharmacological inhibitors (LY294002, U0126), immunohistochemistry of asthmatic biopsies","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway confirmed by multiple inhibitors, receptor expression and function established, single lab","pmids":["21205894"],"is_preprint":false},{"year":2011,"finding":"IL-22 inhibits IL-13-mediated enhancement of IL-25 expression in lung epithelial cells (MLE-15). Anti-IL-22 antibody in vivo enhanced allergen-induced IL-25 production in airways; anti-IL-25 antibody reversed the enhancing effect of IL-22 blockade on eosinophil recruitment. This places IL-22 upstream of IL-25 in a regulatory axis.","method":"Anti-IL-22 neutralization in vivo, intranasal recombinant IL-22 administration, in vitro lung epithelial cell stimulation with IL-22 and IL-13, cytokine measurement by PCR and ELISA","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal antibody blockade in vivo plus in vitro mechanistic confirmation, pathway epistasis established, single lab","pmids":["21794904"],"is_preprint":false},{"year":2013,"finding":"IL-25 induces pulmonary fibrosis via IL-13 release from ILC2s driving collagen deposition in the lungs. ILC2-derived IL-13 is sufficient to drive fibrosis, independently of T-cell-mediated adaptive immunity.","method":"Murine IL-25 administration model, ILC2 characterization, collagen deposition histology, Rag−/− and RORα-deficient mice, cytokine neutralization","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway (IL-25→ILC2→IL-13→fibrosis) confirmed with immunodeficient mice and neutralization, replicated across approaches","pmids":["24344271"],"is_preprint":false},{"year":2013,"finding":"IL-25 predominantly promotes MPPtype2 cell responses rather than ILC2 responses at multiple tissue sites. MPPtype2 cells are distinguished from ILC2 by differential transcription factor requirements, distinct genome-wide transcriptional profile, lack of T1/ST2 and IL-7Rα expression, and multipotent functional potential. IL-25-induced MPPtype2 cells promote Th2 cytokine-associated inflammation after ILC2 depletion.","method":"Comparative in vivo IL-25 vs IL-33 administration, flow cytometry, genome-wide transcriptional profiling, adoptive transfer after ILC2 depletion, transcription factor-deficient mice","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide profiling plus adoptive transfer and genetic epistasis, distinguishing IL-25-specific from IL-33-specific innate responses","pmids":["23960191"],"is_preprint":false},{"year":2014,"finding":"IL-25 receptor (IL-17RB) blockade in mice reduces rhinovirus (RV)-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. RV infection induces IL-25 expression in mouse airways and augments allergen-induced IL-25, positioning IL-25 as a key mediator of RV-induced exacerbation of pulmonary inflammation.","method":"Murine RV infection model, IL-25R neutralizing antibody blockade, cytokine gene expression, cell recruitment quantification","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor blockade in vivo with multiple downstream readouts, RV induction confirmed in both mouse and human cells","pmids":["25273095"],"is_preprint":false},{"year":2014,"finding":"Anti-IL-25 neutralizing antibody treatment in neonatal rhinovirus-infected mice attenuates ILC2 expansion, mucous hypersecretion, and airways hyperresponsiveness, establishing IL-25 as the driver of an age-dependent, ILC2-mediated type 2 response to early-life viral infection.","method":"Neonatal mouse RV infection model, anti-IL-25 neutralization, flow cytometry for ILC2, histology for mucus, methacholine responsiveness","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody blockade in vivo with specific ILC2 expansion and functional readouts, single lab","pmids":["24910174"],"is_preprint":false},{"year":2015,"finding":"Intestinal tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria. After helminth infection, tuft-cell-derived IL-25 activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, forming a response circuit mediating epithelial remodelling.","method":"Tuft-cell-specific IL-25 expression analysis, helminth infection model, ILC2 characterization, IL-13 neutralization, intestinal epithelial progenitor differentiation assays, lineage-tracing/flow cytometry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific origin defined, circuit validated with IL-13 neutralization and progenitor differentiation assays; highly cited foundational study","pmids":["26675736"],"is_preprint":false},{"year":2015,"finding":"IL-25 receptor signaling requires TRAF4, which recruits E3-ligase SMURF2 to degrade the inhibitory molecule DAZAP2, enabling ACT1 interaction with IL-17RB. TRAF4 is required for the ACT1/IL-25R interaction; Traf4−/− mice show blunted IL-25-induced airway eosinophilia and Th2 cytokine production. A specific tyrosine residue within IL-25R is required for DAZAP2-mediated inhibition relief.","method":"Traf4−/− mouse model, in vitro knockdown of Dazap2, co-immunoprecipitation (TRAF4/SMURF2/DAZAP2), in vivo IL-25 challenge, cytokine and eosinophil measurement, site-directed mutagenesis of IL-17RB tyrosine","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — KO mouse in vivo, Co-IP identifying protein complex, mutagenesis of receptor, silencing of inhibitor; multiple orthogonal methods in single study","pmids":["25681341"],"is_preprint":false},{"year":2015,"finding":"IL-25 signals through a novel Act1-independent STAT5 pathway. STAT5 is directly activated by IL-25 and is recruited to IL-17RB in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Conditional STAT5 deletion in T cells or epithelial cells leads to defective IL-25-initiated Th2 polarization.","method":"STAT5 conditional knockout mice (T cell and epithelial specific), STAT5 activation assays, receptor co-immunoprecipitation, site-directed mutagenesis of IL-17RB tyrosines, in vitro Th2 polarization assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — receptor mutagenesis, Co-IP, conditional KO cells, defines novel Act1-independent signaling branch; multiple orthogonal methods","pmids":["25821217"],"is_preprint":false},{"year":2015,"finding":"Keratinocyte-derived IL-17E (IL-25) is increased in psoriatic plaques. Macrophages take up IL-17E via receptor-mediated clathrin-dependent endocytosis rather than synthesizing it. M2 polarized macrophages (not M1) express the IL-17E receptor and respond to IL-17E by producing inflammatory cytokines and chemokines involved in neutrophil recruitment.","method":"Immunohistochemistry of psoriatic skin biopsies, in vitro monocyte-derived macrophage polarization, endocytosis assays (clathrin inhibitor), cytokine/chemokine ELISA","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-mediated endocytosis mechanism defined with inhibitor, M2-specific receptor expression and function confirmed, single lab","pmids":["27329229"],"is_preprint":false},{"year":2017,"finding":"IL-25 promotes M2 macrophage polarization, increases mitochondrial respiratory chain complex I and II/III activity and NAD+/NADH and ATP production, activates AMPK, and induces mitophagy to stimulate M2 macrophage polarization. CCL-22 secretion induced by IL-25 is suppressed by mitophagy inhibitor treatment and PINK1 knockdown.","method":"Human monocyte cell line THP-1, flow cytometry for ROS, ELISA for CCL-22, Western blot for AMPK/mitophagy proteins, confocal microscopy, mitochondrial complex activity assays, PINK1 knockdown","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PINK1 knockdown and mitophagy inhibitor mechanistically link IL-25 to M2 polarization via AMPK-mitophagy axis, multiple readouts, single lab","pmids":["35008429"],"is_preprint":false},{"year":2018,"finding":"IL-25 enhances TH17-cell-mediated contact hypersensitivity by stimulating IL-1β production from dermal dendritic cells. Mast cell- and non-immune cell-derived IL-25 drives hapten-specific TH17 (not TH2) cell activation in the elicitation phase of contact hypersensitivity via IL-1β from dermal DCs.","method":"Il25−/− mice, CHS model (FITC), flow cytometry, ELISA for IL-1β, immunohistochemistry, bone marrow transfer experiments","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — IL-25 KO mice with mechanistic pathway (IL-25→dermal DC→IL-1β→TH17) identified, multiple cellular and molecular readouts","pmids":["29522843"],"is_preprint":false},{"year":2019,"finding":"IL-25 (IL-17E) induces skin inflammation in vivo characterized by innate immune gene expression and neutrophil recruitment. Genetic deletion or neutralization of IL-17E ameliorates imiquimod- or tape stripping-induced skin inflammation. IL-25 promotes neutrophil recruitment via macrophage activation through a p38-dependent mechanism.","method":"Il17e−/− mice, IL-17E neutralization, imiquimod and tape stripping skin inflammation models, multi-parameter flow cytometry (tSNE-guided), in vitro macrophage-neutrophil co-culture with p38 inhibition","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO and neutralization in multiple models, mechanistic pathway (IL-17E→macrophage p38→neutrophil recruitment) confirmed in vitro","pmids":["30738055"],"is_preprint":false},{"year":2020,"finding":"IL-17E (IL-25) promotes keratinocyte proliferation in 2D and 3D cultures and upregulates differentiation-associated gene transcripts (e.g., keratin 10). IL-17E increases keratinocyte cell speed and displacement, associated with changes in actin cytoskeleton organization and cell-substrate adhesion. Human keratinocytes display a complete IL-17E receptor whose expression is induced by IL-17A. IL-22 enhances IL-17E production in keratinocytes.","method":"Primary human keratinocyte culture, 2D and 3D proliferation assays, time-lapse microscopy, actin staining, flow cytometry for receptor expression, gene expression profiling","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts in primary cells, autocrine receptor loop established, single lab","pmids":["31958433"],"is_preprint":false},{"year":2020,"finding":"Keratinocyte-derived IL-25 activates ILC2s to produce IL-13, which drives epidermal hyperplasia, dermal CD4+ T cell infiltration, and expression of IL-13-dependent chemokines (Ccl17, Ccl22) at sites of allergic skin inflammation. ILCs are the major source of IL-13 in acutely sensitized skin, whereas T cells dominate in chronic sensitization.","method":"Mice lacking IL-25R, keratinocyte-specific IL-25 deletion, ILC-specific IL-25R deletion, IL-13 reporter mice (Il13-eGFP), flow cytometry, RT-qPCR, histology, OVA epicutaneous sensitization model","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockouts, IL-13 reporter, and receptor-specific deletions; mechanistic pathway fully traced","pmids":["32179159"],"is_preprint":false},{"year":2020,"finding":"mTOR suppresses autophagy-mediated production of IL-25 in airway epithelial cells. Allergen-induced mTOR downregulation and LC3B-dependent autophagy increase IL-25 production. MTOR-specific knockdown in bronchial epithelium augments, while LC3B deletion abolishes, allergen-induced IL-25 and subsequent airway inflammation. Blocking IL-25 attenuates exacerbated inflammation in mTOR-deficient mice.","method":"Airway epithelium-specific MTOR knockdown mice, lc3b−/− mice, allergen (OVA, HDM) challenge models, human bronchial epithelial cell assays, cytokine measurement, histology","journal":"Thorax","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO mouse systems (MTOR-KD and LC3B-KO), in vivo IL-25 rescue blockade, mechanistic pathway established","pmids":["33077617"],"is_preprint":false},{"year":2021,"finding":"Airway tuft cell-derived cysteinyl leukotrienes (CysLTs, specifically LTC4) and IL-25 synergistically activate ILC2s (for proliferation and cytokine production) and dendritic cells to drive type 2 lung inflammation. Tuft cell-specific deletion of Ltc4s (required for CysLT production) reduces lung inflammation and systemic immune response after aeroallergen inhalation; concomitant IL-25 blockade further enhances this reduction. LTC4-induced eosinophilia is dominantly through CysLT1R, while type 2 cytokines and innate cell activation require both CysLT1R and CysLT2R.","method":"Tuft cell-specific Ltc4s deletion, IL-25 blockade, CysLT receptor pharmacological dissection, intranasal LTC4 + subthreshold IL-25 co-administration, flow cytometry, eosinophil quantification","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic deletion of LTC4 synthase plus IL-25 blockade, synergy experiment with defined receptor pathways, multiple readouts","pmids":["34932383"],"is_preprint":false},{"year":2025,"finding":"IL-17E (IL-25), expressed in cortical neurons, enhances social interaction behavior by acting on IL-17RA- and IL-17RB-expressing neurons in the cortex. IL-17RB—but not IL-17RC—is expressed in the cortex and mediates social behavior effects. Brain-region-specific mapping revealed cortically restricted expression of IL-17RB.","method":"Brain-wide receptor expression mapping, genetic deletion of IL-17RB, social behavior assays, neuronal cell-type-specific expression analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor expression mapping plus genetic deletion with behavioral phenotype, novel neuroimmune function, single study","pmids":["40199322"],"is_preprint":false}],"current_model":"IL-25 (IL-17E) is a cytokine of the IL-17 family produced predominantly by epithelial tuft cells that signals through a heterodimeric receptor composed of IL-17RA and IL-17RB; receptor engagement activates NF-κB via TRAF6, MAPK cascades (ERK, JNK, p38), and a novel Act1-independent STAT5 branch (requiring specific IL-17RB tyrosines), with TRAF4-SMURF2-mediated DAZAP2 degradation enabling ACT1 recruitment; downstream, IL-25 drives type 2 immunity by inducing IL-4, IL-5, IL-13, and IL-9 from ILC2s, MPPtype2 progenitors, Th2 cells, and Th9 cells, while also promoting M2 macrophage polarization via AMPK-mitophagy signaling, suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23/IL-1β/IL-6, stimulating angiogenesis via endothelial PI3K/Akt and ERK/MAPK-VEGF signaling, promoting keratinocyte proliferation and motility, and mediating innate skin inflammation through macrophage p38-dependent neutrophil recruitment; in the intestine, tuft-cell-derived IL-25 forms a feed-forward circuit with ILC2-derived IL-13 to drive goblet and tuft cell differentiation, and IL-25 also functions as a neuromodulatory signal in cortical neurons regulating social behavior through IL-17RB."},"narrative":{"mechanistic_narrative":"IL-25 (IL-17E) is an epithelial- and tuft-cell-derived cytokine of the IL-17 family that serves as a master initiator of type 2 immunity, signaling through the receptor IL-17RB (IL-17BR/EVI27) to drive IL-4, IL-5, and IL-13 production, eosinophilia, IgE responses, and barrier-tissue inflammation [PMID:11058597, PMID:11754819, PMID:26675736]. Receptor engagement activates NF-κB via constitutively associated TRAF6 and parallel ERK/JNK/p38 MAPK cascades to induce proinflammatory chemokines and Th2-skewing genes [PMID:11058597, PMID:16393988]; ACT1 recruitment to IL-17RB requires TRAF4, which directs SMURF2-mediated degradation of the inhibitor DAZAP2, while a distinct set of IL-17RB tyrosines supports a parallel Act1-independent STAT5 branch essential for Th2 polarization [PMID:25681341, PMID:25821217]. IL-25 acts on a range of innate effectors—ILC2s, multipotent MPPtype2 progenitors, Th2 and Th9 cells—to amplify type 2 cytokines, with ILC2-derived IL-13 sufficient to drive airway hyperresponsiveness, fibrosis, and epithelial remodeling [PMID:20200520, PMID:20154671, PMID:24344271, PMID:23960191, PMID:26675736]. In the intestine, tuft-cell-derived IL-25 establishes a feed-forward circuit with ILC2-derived IL-13 that drives tuft and goblet cell differentiation and anti-helminth immunity [PMID:26675736]. Beyond type 2 immunity, IL-25 restrains Th17 responses by inducing IL-13 that suppresses dendritic-cell IL-23/IL-1β/IL-6, defining an IL-25–IL-23–IL-17 axis shaped by commensal microbiota [PMID:17200411, PMID:18762568]; it also promotes M2 macrophage polarization, keratinocyte proliferation and motility, endothelial angiogenesis via VEGF, and innate skin inflammation through macrophage p38-dependent neutrophil recruitment [PMID:21205894, PMID:35008429, PMID:30738055, PMID:31958433]. Epithelial IL-25 production is itself gated by mTOR-suppressed autophagy and modulated by IL-22 and protease allergens [PMID:20514301, PMID:21794904, PMID:33077617]. A recent finding extends IL-25 to neuromodulation, where cortical-neuron-derived IL-17E acts on IL-17RB-expressing cortical neurons to regulate social behavior [PMID:40199322].","teleology":[{"year":2001,"claim":"Establishing that IL-25 is a functional ligand for IL-17RB that triggers NF-κB and chemokine output defined its molecular identity as a signaling cytokine.","evidence":"Receptor-ligand binding, NF-κB reporter, and IL-8 production assays in vitro","pmids":["11058597"],"confidence":"High","gaps":["Did not define the second receptor chain or the downstream adaptor","Physiological cellular source not addressed"]},{"year":2001,"claim":"In vivo infusion and transgenic overexpression showed IL-25 is sufficient to drive a systemic Th2 cytokine cascade, IgE responses, and eosinophilia, framing it as an initiator of type 2 immunity.","evidence":"Cytokine infusion and transgenic mouse models with serum Ig, cytokine, histology, and flow readouts","pmids":["11754819","11714825","12239140"],"confidence":"High","gaps":["Lineage-negative responding cell identity left undefined","Did not resolve direct versus indirect cytokine induction"]},{"year":2002,"claim":"Genetic epistasis placed IL-5 and IL-13 (not IL-4 or T cells) as the obligate downstream effectors of IL-25-induced eosinophilia, narrowing the effector arm.","evidence":"Adenoviral IL-25 delivery in cytokine- and T-cell-deficient mice with BAL and flow analysis","pmids":["12077275"],"confidence":"High","gaps":["Identity of the gamma-common-dependent innate responder cell not resolved","Did not address receptor signaling mechanism"]},{"year":2006,"claim":"Identifying TRAF6 as the constitutively associated adaptor required for IL-25R-driven NF-κB and demonstrating MAPK activation defined the proximal signaling machinery.","evidence":"Receptor cross-linking, dominant-negative and TRAF6-deficient MEFs, reciprocal Co-IP, gene expression","pmids":["16393988"],"confidence":"High","gaps":["Role of ACT1 and receptor tyrosines not yet defined","Did not address non-NF-κB branches"]},{"year":2006,"claim":"Demonstrating that lung fibroblasts and airway smooth muscle constitutively express IL-17BR and respond to IL-25 with chemokine and ECM gene induction, with receptor levels tuned by TNF-α and IFN-γ, extended IL-25 action to structural cells.","evidence":"Primary fibroblast and airway smooth muscle cultures, pharmacological pathway inhibitors, PCR/ELISA","pmids":["16522458","16428271"],"confidence":"Medium","gaps":["Single-lab findings","In vivo relevance of ECM induction not established"]},{"year":2007,"claim":"STAT6- and CD4-dependent epistasis plus discovery that IL-25 suppresses Th17 responses via IL-13-mediated inhibition of dendritic-cell IL-23 revealed IL-25 as both a type 2 amplifier and a Th17 brake.","evidence":"STAT6 KO, CD4 depletion, transgenic and IL-25 KO mice in airway and EAE models with DC stimulation assays","pmids":["17177681","16950278","17200411","17719653"],"confidence":"High","gaps":["Receptor-level basis of STAT6 engagement not defined","Cell-type source of protective IL-25 in EAE unresolved"]},{"year":2008,"claim":"Commensal-dependent suppression of epithelial IL-25 in the gut defined an IL-25–IL-23–IL-17 regulatory axis tuned by microbiota, situating IL-25 in intestinal immune homeostasis.","evidence":"Germ-free mouse model with epithelial sorting, cytokine quantification, T-cell flow cytometry","pmids":["18762568"],"confidence":"High","gaps":["Molecular sensor linking microbiota to IL-25 repression unknown","Macrophage-IL-23 step not mechanistically dissected"]},{"year":2010,"claim":"Discovery that IL-25 expands MPPtype2 progenitors and couples to IL-17RB on Th9 cells to drive IL-9 broadened the cellular targets of IL-25 beyond classical Th2 cells.","evidence":"Flow cytometry, adoptive transfer into Il25-/- mice, retroviral/transgenic IL-17RB overexpression, helminth and airway models","pmids":["20200520","20154671"],"confidence":"High","gaps":["Relationship between MPPtype2 and ILC2 not yet resolved","Signaling basis of IL-9 induction unaddressed"]},{"year":2010,"claim":"Identifying protease-allergen activation of ERK/p38 as the trigger for epithelial IL-25 induction connected environmental sensing to IL-25 output.","evidence":"Lung epithelial cell stimulation with protease-inactivation controls and MAPK inhibitors plus in vivo BAL","pmids":["20514301"],"confidence":"Medium","gaps":["Protease receptor/sensor not identified","Single-lab finding"]},{"year":2013,"claim":"Demonstrating that IL-25-activated ILC2-derived IL-13 is sufficient to drive fibrosis independent of T cells, and that IL-25 preferentially drives MPPtype2 over ILC2 responses, refined the innate effector hierarchy.","evidence":"IL-25 administration in Rag-/- and RORα-deficient mice, genome-wide profiling, adoptive transfer after ILC2 depletion","pmids":["24344271","23960191"],"confidence":"High","gaps":["Determinants of ILC2 versus MPPtype2 preference unclear","Receptor signaling distinguishing the two not defined"]},{"year":2014,"claim":"Receptor blockade and IL-25 neutralization in rhinovirus models established IL-25 as a driver of viral exacerbation of type 2 airway inflammation, including an age-dependent ILC2 response.","evidence":"Murine RV infection with IL-17RB blockade or anti-IL-25, cell recruitment and ILC2 flow cytometry","pmids":["25273095","24910174"],"confidence":"High","gaps":["Mechanism by which RV induces epithelial IL-25 not fully defined","Human translation not directly tested in vivo"]},{"year":2015,"claim":"Defining the tuft-cell origin of IL-25 and the tuft–ILC2–IL-13 feed-forward circuit established the cellular architecture of intestinal type 2 epithelial remodeling.","evidence":"Tuft-cell IL-25 expression, helminth infection, IL-13 neutralization, epithelial progenitor differentiation assays","pmids":["26675736"],"confidence":"High","gaps":["Tuft cell sensing input upstream of IL-25 not defined here","Receptor signaling in ILC2 not dissected"]},{"year":2015,"claim":"Identifying the TRAF4-SMURF2-DAZAP2 axis enabling ACT1 recruitment and a parallel Act1-independent STAT5 branch through specific IL-17RB tyrosines resolved the bifurcated proximal signaling of IL-25.","evidence":"Traf4-/- and STAT5 conditional KO mice, Co-IP of TRAF4/SMURF2/DAZAP2, IL-17RB tyrosine mutagenesis, Th2 polarization assays","pmids":["25681341","25821217"],"confidence":"High","gaps":["Structural basis of tyrosine-specific STAT5 recruitment unresolved","Cell-type specificity of the two branches not fully mapped"]},{"year":2016,"claim":"Demonstrating receptor-mediated clathrin-dependent uptake of IL-25 by M2 macrophages, and selective caspase-driven apoptosis in IL-17RB-high breast cancer cells, expanded IL-25 biology to non-canonical receptor responses and tumor contexts.","evidence":"Psoriatic biopsy IHC, macrophage polarization and endocytosis assays, 3D breast cancer cultures with caspase assays","pmids":["27329229","21490275"],"confidence":"Medium","gaps":["Signaling downstream of endocytosed IL-25 not defined","Single-lab findings"]},{"year":2017,"claim":"Linking IL-25-driven M2 polarization to AMPK activation and PINK1-dependent mitophagy provided a metabolic mechanism for macrophage reprogramming.","evidence":"THP-1 monocytes with mitochondrial complex assays, AMPK/mitophagy Western blots, PINK1 knockdown, CCL-22 ELISA","pmids":["35008429"],"confidence":"Medium","gaps":["Receptor-to-AMPK coupling not defined","Single cell-line system"]},{"year":2019,"claim":"Genetic and neutralization studies established IL-25 as a driver of innate skin inflammation, keratinocyte proliferation/motility, angiogenesis, and Th17-mediated contact hypersensitivity via diverse effector mechanisms.","evidence":"Il17e-/- mice, neutralization in imiquimod/tape-stripping and CHS models, macrophage-neutrophil co-culture with p38 inhibition, HUVEC angiogenesis, keratinocyte cultures","pmids":["30738055","29522843","31958433","21205894"],"confidence":"High","gaps":["Receptor signaling underlying keratinocyte and endothelial responses not fully mapped","Context determining type 2 versus type 17 output unclear"]},{"year":2020,"claim":"Defining keratinocyte-derived IL-25 as an ILC2-activating trigger of allergic skin inflammation, and showing mTOR-suppressed autophagy gates epithelial IL-25 production, connected barrier IL-25 output to upstream regulation and downstream type 2 pathology.","evidence":"Cell-type-specific IL-25/IL-17RB conditional KO and IL-13 reporter mice; airway MTOR-KD and Lc3b-/- mice with IL-25 blockade","pmids":["32179159","33077617"],"confidence":"High","gaps":["Signal linking autophagy to IL-25 transcription/secretion not defined","Acute versus chronic IL-13 source switch mechanism unresolved"]},{"year":2021,"claim":"Showing that tuft-cell cysteinyl leukotrienes and IL-25 synergistically activate ILC2s and dendritic cells revealed combinatorial epithelial signals shaping type 2 lung inflammation.","evidence":"Tuft-cell-specific Ltc4s deletion, IL-25 blockade, CysLT receptor pharmacology, LTC4 plus subthreshold IL-25 co-administration","pmids":["34932383"],"confidence":"High","gaps":["Molecular basis of LTC4/IL-25 synergy at the ILC2 level not defined"]},{"year":2025,"claim":"Identifying cortical-neuron-derived IL-25 acting on IL-17RB-expressing cortical neurons to regulate social behavior extended IL-25 into neuromodulation beyond immunity.","evidence":"Brain-wide receptor mapping, genetic IL-17RB deletion, social behavior assays","pmids":["40199322"],"confidence":"Medium","gaps":["Neuronal signaling pathway downstream of IL-17RB not defined","Single-study novel function awaiting independent confirmation"]},{"year":null,"claim":"How distinct IL-17RB tyrosine-coupled branches (TRAF6/ACT1 NF-κB versus STAT5) are differentially deployed across cell types, and how upstream sensors gate IL-25 release in epithelial, neuronal, and tumor contexts, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the ligand-receptor-adaptor assembly","Cell-type logic of branch selection unresolved","Sensor coupling autophagy/protease/microbiota to IL-25 transcription incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,27]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,25]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,12,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,26,27]}],"complexes":[],"partners":["IL17RB","IL17RA","TRAF6","TRAF4","SMURF2","DAZAP2","ACT1","STAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H293","full_name":"Interleukin-25","aliases":["Interleukin-17E","IL-17E"],"length_aa":177,"mass_kda":20.3,"function":"Cytokine produced by various cells such as eosinophils, T-helper type 2 (Th2) cells or epithelial cells that plays a role in internal safety of adaptive immune responses by regulating cytokine production (PubMed:15860795, PubMed:25821217). Promotes and augments T-helper type 2 responses locally or systemically (PubMed:25821217). Exerts its activity via its receptor composed of IL17RA and IL17RB for signal transduction (By similarity). In turn, stimulates the JAK2-STAT5A pathway and promotes the secretion of type-2 associated cytokines including IL4, IL9 and IL13 (PubMed:25821217). Also induces the release of IL8, and IL6 from eosinophils through the combined activation of MAPK and NF-kappa-B pathways (PubMed:15860795). Inhibits the differentiation of T-helper (Th17) cells via the production of IL4, IL5 and IL13 (PubMed:11754819)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9H293/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL25","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL25","total_profiled":1310},"omim":[{"mim_id":"616445","title":"CANDIDIASIS, FAMILIAL, 9; CANDF9","url":"https://www.omim.org/entry/616445"},{"mim_id":"613953","title":"IMMUNODEFICIENCY 51; IMD51","url":"https://www.omim.org/entry/613953"},{"mim_id":"610925","title":"INTERLEUKIN 17 RECEPTOR C; IL17RC","url":"https://www.omim.org/entry/610925"},{"mim_id":"608678","title":"INTERLEUKIN 33; IL33","url":"https://www.omim.org/entry/608678"},{"mim_id":"607394","title":"POU DOMAIN, CLASS 2, TRANSCRIPTION FACTOR 3; POU2F3","url":"https://www.omim.org/entry/607394"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL25"},"hgnc":{"alias_symbol":["IL-25","IL-17E"],"prev_symbol":["IL17E"]},"alphafold":{"accession":"Q9H293","domains":[{"cath_id":"2.10.90.10","chopping":"74-137_164-177","consensus_level":"medium","plddt":94.7309,"start":74,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H293","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H293-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H293-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL25","jax_strain_url":"https://www.jax.org/strain/search?query=IL25"},"sequence":{"accession":"Q9H293","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H293.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H293/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H293"}},"corpus_meta":[{"pmid":"26675736","id":"PMC_26675736","title":"Tuft-cell-derived 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Binding induces NF-κB activation and stimulates production of the proinflammatory chemokine IL-8.\",\n      \"method\": \"Receptor-ligand binding assay, NF-κB reporter assay, IL-8 production assay in vitro\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct receptor identification with functional NF-κB and cytokine readouts in a focused mechanistic study\",\n      \"pmids\": [\"11058597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Infusion of IL-25 into mice induced IL-4, IL-5, and IL-13 gene expression and Th2-like responses (elevated serum IgE, IgG1, IgA, blood eosinophilia, lung and gut pathology). IL-25 induced Th2-type cytokine production by MHC class II-high, CD11c-dull, lineage-negative accessory cells.\",\n      \"method\": \"In vivo cytokine infusion in mice, gene expression analysis, serum immunoglobulin measurement, histology, flow cytometry of responding cell populations\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined cellular targets and downstream cytokine cascade in vivo, replicated across multiple readouts\",\n      \"pmids\": [\"11754819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Transgenic overexpression of murine IL-17E induces a Th2-biased immune response characterized by eosinophilia, elevated serum IL-13 and IL-5, increased IgE/IgG1, and multi-organ inflammatory pathology. IL-17E also induces G-CSF production in vitro and neutrophilia in vivo.\",\n      \"method\": \"Transgenic mouse model, serum cytokine and immunoglobulin measurement, histology, in vitro G-CSF assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with multiple orthogonal readouts establishing downstream cytokine cascade\",\n      \"pmids\": [\"11714825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Intranasal IL-25 induces IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia. IL-25-induced eosinophilia requires IL-5 and IL-13 but not IL-4 or T cells, and requires a gamma-common cytokine receptor-dependent cell population that is B220+, Thy-1+/-, NK1.1-, Ly-6G-, CD4-, CD3-, c-kit-negative.\",\n      \"method\": \"Adenoviral in vivo delivery, cytokine-deficient and T-cell-deficient mouse models, flow cytometry of responding cell populations, bronchoalveolar lavage analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis using multiple cytokine-deficient mouse lines, defined downstream requirement for IL-5 and IL-13\",\n      \"pmids\": [\"12077275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Transgenic overexpression of human IL-17E in mice driven by ApoE hepatic promoter causes eosinophilia, B-lymphocyte hyperplasia, elevated serum IL-2, IL-4, IL-5, G-CSF, eotaxin, IFN-γ, and increased IgM, IgG, IgE. In situ hybridization revealed upregulation of the IL-17E receptor IL-17Rh1 (IL-17BR/Evi27) in transgenic tissues.\",\n      \"method\": \"Transgenic mouse model (ApoE promoter), flow cytometry, serum cytokine/immunoglobulin ELISA, in situ hybridization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with multiple orthogonal readouts, receptor upregulation confirmed by ISH\",\n      \"pmids\": [\"12239140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-25R (IL-17RB) cross-linking activates NF-κB and MAPK pathways (ERK, JNK, p38). NF-κB activation is mediated specifically by TRAF6 (not TRAF2): dominant-negative TRAF6 blocked IL-25R-mediated NF-κB activation, and NF-κB activation was absent in TRAF6-deficient fibroblasts. TRAF6 co-immunoprecipitates with IL-25R even in the absence of ligand. TRAF6 is required for IL-25R-mediated gene expression of IL-6, TGF-β, G-CSF, and TARC.\",\n      \"method\": \"Receptor cross-linking assay, dominant-negative transfection, TRAF6-deficient murine embryonic fibroblasts, co-immunoprecipitation, NF-κB reporter assay, gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, dominant-negative and KO cell systems, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"16393988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-17E (IL-25) upregulates CCL5, CCL11 (eotaxin), GM-CSF, and CXCL8 mRNA in human primary lung fibroblasts, which constitutively express IL-17BR. IL-17E and TNF-α synergistically induce GM-CSF and CXCL8 production and secretion. TGF-β1 modulates IL-17E-induced responses. IL-17BR mRNA is upregulated by TNF-α and downregulated by TGF-β1.\",\n      \"method\": \"Primary fibroblast culture, immunofluorescence, Western blot, real-time PCR, ELISA, cytokine stimulation\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor expression confirmed by multiple methods, functional cytokine induction in primary cells, single lab\",\n      \"pmids\": [\"16522458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TNF-α upregulates IL-17BR expression in airway smooth muscle cells primarily through NF-κB (blocked by IKK2 inhibitor AS-602868). IFN-γ downregulates IL-17BR via the ERK pathway (blocked by MEK inhibitor U0126). IL-17E stimulation of airway smooth muscle cells increases expression of ECM components procollagen-αI and lumican mRNA.\",\n      \"method\": \"In vitro airway smooth muscle cell culture, pharmacological inhibitors (NF-κB, MEK/ERK), real-time PCR, Western blot, immunohistochemistry of asthmatic biopsies\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of signaling pathway with multiple inhibitors, ECM induction confirmed, single lab\",\n      \"pmids\": [\"16428271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-25-induced airway hyperresponsiveness (AHR) and eosinophilic inflammation are dependent on IL-13, IL-4Rα (IL-4 receptor alpha), and STAT6 signaling, as shown by significantly reduced AHR and mucus production in IL-13−/−, IL-4Rα−/−, and STAT6−/− mice. IL-4 and IL-5/eotaxin1 deficiency also reduced AHR but not mucus hypersecretion. IL-25 can directly act on naïve T cells to promote Th2 responses.\",\n      \"method\": \"Intratracheal IL-25 instillation in cytokine-deficient mouse strains, plethysmography, histology, BAL analysis\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using multiple cytokine and signaling pathway KO mouse lines with defined phenotypic readouts\",\n      \"pmids\": [\"17177681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-25-deficient mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE), associated with increased IL-23 in the periphery and increased IL-17-, IFN-γ-, and TNF-producing T cells. IL-25 suppresses Th17 responses by inducing IL-13, which directly inhibits IL-23, IL-1β, and IL-6 expression in activated dendritic cells.\",\n      \"method\": \"IL-25 knockout mice, EAE model, cytokine neutralization (anti-IL-17, anti-IFN-γ), IL-25 treatment in relapsing-remitting and chronic EAE models, dendritic cell stimulation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IL-25 KO mice plus pharmacological neutralization epistasis, defined mechanism through IL-13→dendritic cell IL-23 suppression\",\n      \"pmids\": [\"17200411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-25 enhances antigen-induced Th2 cytokine production, eosinophil recruitment, and goblet cell hyperplasia in allergic airway inflammation through a Th2 cell-dependent pathway requiring CD4+ T cells and STAT6. Transgenic enforced expression of IL-25 in lung (Clara cell promoter) alone is insufficient to induce inflammation but potentiates allergen-driven responses.\",\n      \"method\": \"IL-25 transgenic mice (CC10 promoter), CD4+ T cell depletion, STAT6-deficient mice, OVA sensitization model, BAL analysis, histology\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic model plus genetic epistasis (T cell depletion, STAT6 KO), multiple orthogonal readouts\",\n      \"pmids\": [\"16950278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-25 synergistically induces release of Th2 cytokines (IL-4, IL-5, IL-10), IL-6, and chemokines (CXCL9, CXCL10, CCL5) from anti-CD3/CD28 costimulated human memory Th cells. Costimulation upregulates IL-25R surface expression on Th cells. The cytokine release is differentially regulated by JNK, p38 MAPK, and NF-κB pathways.\",\n      \"method\": \"Human T cell culture with anti-CD3/CD28 costimulation and IL-25, bead-based multiplex cytokine array, flow cytometry for receptor expression, EMSA for NF-κB, Western blot for MAPK, pharmacological inhibitors\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway inhibitors and receptor measurement in primary human cells, single lab\",\n      \"pmids\": [\"17719653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Commensal bacteria suppress intestinal IL-25 expression by intestinal epithelial cells. In germ-free mice, elevated Th17 cell frequency in the large intestine is associated with reduced IL-25. Commensal-dependent IL-25 limits expansion of Th17 cells by inhibiting macrophage-derived IL-23, defining an IL-25–IL-23–IL-17 axis.\",\n      \"method\": \"Germ-free mouse model, microbiota colonization, epithelial cell sorting, cytokine quantification, T cell frequency by flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germ-free model plus mechanistic pathway (IL-25→IL-23 inhibition→Th17 suppression) with multiple cell-type readouts\",\n      \"pmids\": [\"18762568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Allergen-induced stem cell factor (SCF) promotes IL-25 (IL-17E) production from c-kit+ eosinophils in the lung; bone marrow-derived mast cells did not produce IL-25 in response to SCF. The IL-25R (IL-17RB) was expressed on a CD11b+GR1+Ly6C+/- c-kit- myeloid cell population that is the major source of Th2 cytokines (IL-4) in the lung during chronic allergen challenge.\",\n      \"method\": \"SCF neutralization in allergen-challenged mice, sorted cell populations for cytokine expression, 4get IL-4 reporter mice, flow cytometry, bone marrow-derived mast cell assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell sorting and reporter mouse to identify producing and responding cell populations, single lab\",\n      \"pmids\": [\"19828636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-25 promotes accumulation of a lineage-negative multipotent progenitor (MPPtype2) cell population (Sca-1+, c-Kitint) in gut-associated lymphoid tissue. MPPtype2 cells exhibit multipotent capacity giving rise to monocyte/macrophage and granulocyte lineages in vitro and in vivo. Adoptive transfer of MPPtype2 cells promotes Th2 cytokine responses and confers protective immunity to helminth infection in IL-25-deficient mice.\",\n      \"method\": \"Flow cytometry, in vitro and in vivo differentiation assays, adoptive transfer into Il25−/− mice, helminth infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — adoptive transfer reconstitution, in vitro and in vivo multipotency assays, mechanistic placement via IL-25-deficient mice\",\n      \"pmids\": [\"20200520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-25 signals through IL-17RB expressed on in-vitro-generated IL-9-expressing T cells (Th9 cells) to enhance IL-9 expression. Transgenic or retroviral overexpression of IL-17RB in T cells results in IL-25-induced IL-9 production independently of IL-4. In vivo, the IL-25–IL-17RB pathway regulates IL-9 expression in allergic airway inflammation.\",\n      \"method\": \"In vitro Th9 cell generation, retroviral/transgenic overexpression of IL-17RB, IL-9 cytokine measurement, allergic airway inflammation mouse model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function (retroviral and transgenic overexpression) plus in vivo validation with defined receptor-cytokine coupling\",\n      \"pmids\": [\"20154671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protease allergens (papain, Der P1) induce IL-25 and TSLP gene expression in mouse lung epithelial cells via protease activity-dependent activation of ERK and p38 MAPK pathways, but not NF-κB or PI-3 kinase pathways. Deactivation of protease activity abolishes IL-25 induction.\",\n      \"method\": \"Mouse lung epithelial cell (MLE12) stimulation, protease inactivation controls, pharmacological MAPK inhibitors, real-time PCR, in vivo BAL cytokine measurement\",\n      \"journal\": \"Journal of Korean medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with protease-inactivated controls in epithelial cells plus in vivo confirmation, single lab\",\n      \"pmids\": [\"20514301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-25 enhances survival of human eosinophils and upregulates ICAM-1 surface expression while suppressing ICAM-3 and L-selectin, increasing eosinophil adhesion to fibronectin. These effects are mediated through p38 MAPK (for L-selectin regulation), JNK (for ICAM-1), and NF-κB/proteasome (for ICAM-3) pathways.\",\n      \"method\": \"Human eosinophil culture, flow cytometry for adhesion molecules, fibronectin adhesion assay, pharmacological inhibitors (SB203580, SP600125, MG-132), RT-PCR\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of multiple signaling pathways with functional adhesion readout, single lab\",\n      \"pmids\": [\"16792588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-25 activates caspase-mediated apoptosis in IL-25R (IL-17RB)-expressing breast cancer cells through differential receptor expression; nonmalignant mammary epithelial cells with low IL-17RB expression are spared. IL-17RB is expressed at high levels in tumors from patients with poor prognosis but low in nonmalignant breast tissue.\",\n      \"method\": \"In vitro 3D laminin-rich gel culture, secreted factor screen, caspase activity assays, tumor tissue expression analysis, selective cytotoxicity assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor expression correlated with apoptotic sensitivity, caspase activation confirmed, single lab\",\n      \"pmids\": [\"21490275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-25 stimulates angiogenesis in vitro by increasing HUVEC proliferation and microvessel formation in a concentration-dependent manner. HUVECs constitutively express IL-25R (upregulated by TNF-α). IL-25 increases VEGF and VEGF receptor expression. IL-25-induced angiogenesis is blocked by VEGF neutralization, PI3K inhibitor LY294002, and MEK1/2 inhibitor U0126.\",\n      \"method\": \"In vitro angiogenesis assay (HUVEC), WST-8 proliferation assay, real-time PCR for IL-25R and VEGF, pharmacological inhibitors (LY294002, U0126), immunohistochemistry of asthmatic biopsies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway confirmed by multiple inhibitors, receptor expression and function established, single lab\",\n      \"pmids\": [\"21205894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-22 inhibits IL-13-mediated enhancement of IL-25 expression in lung epithelial cells (MLE-15). Anti-IL-22 antibody in vivo enhanced allergen-induced IL-25 production in airways; anti-IL-25 antibody reversed the enhancing effect of IL-22 blockade on eosinophil recruitment. This places IL-22 upstream of IL-25 in a regulatory axis.\",\n      \"method\": \"Anti-IL-22 neutralization in vivo, intranasal recombinant IL-22 administration, in vitro lung epithelial cell stimulation with IL-22 and IL-13, cytokine measurement by PCR and ELISA\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal antibody blockade in vivo plus in vitro mechanistic confirmation, pathway epistasis established, single lab\",\n      \"pmids\": [\"21794904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-25 induces pulmonary fibrosis via IL-13 release from ILC2s driving collagen deposition in the lungs. ILC2-derived IL-13 is sufficient to drive fibrosis, independently of T-cell-mediated adaptive immunity.\",\n      \"method\": \"Murine IL-25 administration model, ILC2 characterization, collagen deposition histology, Rag−/− and RORα-deficient mice, cytokine neutralization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway (IL-25→ILC2→IL-13→fibrosis) confirmed with immunodeficient mice and neutralization, replicated across approaches\",\n      \"pmids\": [\"24344271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-25 predominantly promotes MPPtype2 cell responses rather than ILC2 responses at multiple tissue sites. MPPtype2 cells are distinguished from ILC2 by differential transcription factor requirements, distinct genome-wide transcriptional profile, lack of T1/ST2 and IL-7Rα expression, and multipotent functional potential. IL-25-induced MPPtype2 cells promote Th2 cytokine-associated inflammation after ILC2 depletion.\",\n      \"method\": \"Comparative in vivo IL-25 vs IL-33 administration, flow cytometry, genome-wide transcriptional profiling, adoptive transfer after ILC2 depletion, transcription factor-deficient mice\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide profiling plus adoptive transfer and genetic epistasis, distinguishing IL-25-specific from IL-33-specific innate responses\",\n      \"pmids\": [\"23960191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-25 receptor (IL-17RB) blockade in mice reduces rhinovirus (RV)-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. RV infection induces IL-25 expression in mouse airways and augments allergen-induced IL-25, positioning IL-25 as a key mediator of RV-induced exacerbation of pulmonary inflammation.\",\n      \"method\": \"Murine RV infection model, IL-25R neutralizing antibody blockade, cytokine gene expression, cell recruitment quantification\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor blockade in vivo with multiple downstream readouts, RV induction confirmed in both mouse and human cells\",\n      \"pmids\": [\"25273095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Anti-IL-25 neutralizing antibody treatment in neonatal rhinovirus-infected mice attenuates ILC2 expansion, mucous hypersecretion, and airways hyperresponsiveness, establishing IL-25 as the driver of an age-dependent, ILC2-mediated type 2 response to early-life viral infection.\",\n      \"method\": \"Neonatal mouse RV infection model, anti-IL-25 neutralization, flow cytometry for ILC2, histology for mucus, methacholine responsiveness\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody blockade in vivo with specific ILC2 expansion and functional readouts, single lab\",\n      \"pmids\": [\"24910174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intestinal tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria. After helminth infection, tuft-cell-derived IL-25 activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, forming a response circuit mediating epithelial remodelling.\",\n      \"method\": \"Tuft-cell-specific IL-25 expression analysis, helminth infection model, ILC2 characterization, IL-13 neutralization, intestinal epithelial progenitor differentiation assays, lineage-tracing/flow cytometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific origin defined, circuit validated with IL-13 neutralization and progenitor differentiation assays; highly cited foundational study\",\n      \"pmids\": [\"26675736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-25 receptor signaling requires TRAF4, which recruits E3-ligase SMURF2 to degrade the inhibitory molecule DAZAP2, enabling ACT1 interaction with IL-17RB. TRAF4 is required for the ACT1/IL-25R interaction; Traf4−/− mice show blunted IL-25-induced airway eosinophilia and Th2 cytokine production. A specific tyrosine residue within IL-25R is required for DAZAP2-mediated inhibition relief.\",\n      \"method\": \"Traf4−/− mouse model, in vitro knockdown of Dazap2, co-immunoprecipitation (TRAF4/SMURF2/DAZAP2), in vivo IL-25 challenge, cytokine and eosinophil measurement, site-directed mutagenesis of IL-17RB tyrosine\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — KO mouse in vivo, Co-IP identifying protein complex, mutagenesis of receptor, silencing of inhibitor; multiple orthogonal methods in single study\",\n      \"pmids\": [\"25681341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-25 signals through a novel Act1-independent STAT5 pathway. STAT5 is directly activated by IL-25 and is recruited to IL-17RB in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Conditional STAT5 deletion in T cells or epithelial cells leads to defective IL-25-initiated Th2 polarization.\",\n      \"method\": \"STAT5 conditional knockout mice (T cell and epithelial specific), STAT5 activation assays, receptor co-immunoprecipitation, site-directed mutagenesis of IL-17RB tyrosines, in vitro Th2 polarization assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — receptor mutagenesis, Co-IP, conditional KO cells, defines novel Act1-independent signaling branch; multiple orthogonal methods\",\n      \"pmids\": [\"25821217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Keratinocyte-derived IL-17E (IL-25) is increased in psoriatic plaques. Macrophages take up IL-17E via receptor-mediated clathrin-dependent endocytosis rather than synthesizing it. M2 polarized macrophages (not M1) express the IL-17E receptor and respond to IL-17E by producing inflammatory cytokines and chemokines involved in neutrophil recruitment.\",\n      \"method\": \"Immunohistochemistry of psoriatic skin biopsies, in vitro monocyte-derived macrophage polarization, endocytosis assays (clathrin inhibitor), cytokine/chemokine ELISA\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-mediated endocytosis mechanism defined with inhibitor, M2-specific receptor expression and function confirmed, single lab\",\n      \"pmids\": [\"27329229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-25 promotes M2 macrophage polarization, increases mitochondrial respiratory chain complex I and II/III activity and NAD+/NADH and ATP production, activates AMPK, and induces mitophagy to stimulate M2 macrophage polarization. CCL-22 secretion induced by IL-25 is suppressed by mitophagy inhibitor treatment and PINK1 knockdown.\",\n      \"method\": \"Human monocyte cell line THP-1, flow cytometry for ROS, ELISA for CCL-22, Western blot for AMPK/mitophagy proteins, confocal microscopy, mitochondrial complex activity assays, PINK1 knockdown\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PINK1 knockdown and mitophagy inhibitor mechanistically link IL-25 to M2 polarization via AMPK-mitophagy axis, multiple readouts, single lab\",\n      \"pmids\": [\"35008429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-25 enhances TH17-cell-mediated contact hypersensitivity by stimulating IL-1β production from dermal dendritic cells. Mast cell- and non-immune cell-derived IL-25 drives hapten-specific TH17 (not TH2) cell activation in the elicitation phase of contact hypersensitivity via IL-1β from dermal DCs.\",\n      \"method\": \"Il25−/− mice, CHS model (FITC), flow cytometry, ELISA for IL-1β, immunohistochemistry, bone marrow transfer experiments\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IL-25 KO mice with mechanistic pathway (IL-25→dermal DC→IL-1β→TH17) identified, multiple cellular and molecular readouts\",\n      \"pmids\": [\"29522843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-25 (IL-17E) induces skin inflammation in vivo characterized by innate immune gene expression and neutrophil recruitment. Genetic deletion or neutralization of IL-17E ameliorates imiquimod- or tape stripping-induced skin inflammation. IL-25 promotes neutrophil recruitment via macrophage activation through a p38-dependent mechanism.\",\n      \"method\": \"Il17e−/− mice, IL-17E neutralization, imiquimod and tape stripping skin inflammation models, multi-parameter flow cytometry (tSNE-guided), in vitro macrophage-neutrophil co-culture with p38 inhibition\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO and neutralization in multiple models, mechanistic pathway (IL-17E→macrophage p38→neutrophil recruitment) confirmed in vitro\",\n      \"pmids\": [\"30738055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17E (IL-25) promotes keratinocyte proliferation in 2D and 3D cultures and upregulates differentiation-associated gene transcripts (e.g., keratin 10). IL-17E increases keratinocyte cell speed and displacement, associated with changes in actin cytoskeleton organization and cell-substrate adhesion. Human keratinocytes display a complete IL-17E receptor whose expression is induced by IL-17A. IL-22 enhances IL-17E production in keratinocytes.\",\n      \"method\": \"Primary human keratinocyte culture, 2D and 3D proliferation assays, time-lapse microscopy, actin staining, flow cytometry for receptor expression, gene expression profiling\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts in primary cells, autocrine receptor loop established, single lab\",\n      \"pmids\": [\"31958433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Keratinocyte-derived IL-25 activates ILC2s to produce IL-13, which drives epidermal hyperplasia, dermal CD4+ T cell infiltration, and expression of IL-13-dependent chemokines (Ccl17, Ccl22) at sites of allergic skin inflammation. ILCs are the major source of IL-13 in acutely sensitized skin, whereas T cells dominate in chronic sensitization.\",\n      \"method\": \"Mice lacking IL-25R, keratinocyte-specific IL-25 deletion, ILC-specific IL-25R deletion, IL-13 reporter mice (Il13-eGFP), flow cytometry, RT-qPCR, histology, OVA epicutaneous sensitization model\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockouts, IL-13 reporter, and receptor-specific deletions; mechanistic pathway fully traced\",\n      \"pmids\": [\"32179159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"mTOR suppresses autophagy-mediated production of IL-25 in airway epithelial cells. Allergen-induced mTOR downregulation and LC3B-dependent autophagy increase IL-25 production. MTOR-specific knockdown in bronchial epithelium augments, while LC3B deletion abolishes, allergen-induced IL-25 and subsequent airway inflammation. Blocking IL-25 attenuates exacerbated inflammation in mTOR-deficient mice.\",\n      \"method\": \"Airway epithelium-specific MTOR knockdown mice, lc3b−/− mice, allergen (OVA, HDM) challenge models, human bronchial epithelial cell assays, cytokine measurement, histology\",\n      \"journal\": \"Thorax\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO mouse systems (MTOR-KD and LC3B-KO), in vivo IL-25 rescue blockade, mechanistic pathway established\",\n      \"pmids\": [\"33077617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Airway tuft cell-derived cysteinyl leukotrienes (CysLTs, specifically LTC4) and IL-25 synergistically activate ILC2s (for proliferation and cytokine production) and dendritic cells to drive type 2 lung inflammation. Tuft cell-specific deletion of Ltc4s (required for CysLT production) reduces lung inflammation and systemic immune response after aeroallergen inhalation; concomitant IL-25 blockade further enhances this reduction. LTC4-induced eosinophilia is dominantly through CysLT1R, while type 2 cytokines and innate cell activation require both CysLT1R and CysLT2R.\",\n      \"method\": \"Tuft cell-specific Ltc4s deletion, IL-25 blockade, CysLT receptor pharmacological dissection, intranasal LTC4 + subthreshold IL-25 co-administration, flow cytometry, eosinophil quantification\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic deletion of LTC4 synthase plus IL-25 blockade, synergy experiment with defined receptor pathways, multiple readouts\",\n      \"pmids\": [\"34932383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17E (IL-25), expressed in cortical neurons, enhances social interaction behavior by acting on IL-17RA- and IL-17RB-expressing neurons in the cortex. IL-17RB—but not IL-17RC—is expressed in the cortex and mediates social behavior effects. Brain-region-specific mapping revealed cortically restricted expression of IL-17RB.\",\n      \"method\": \"Brain-wide receptor expression mapping, genetic deletion of IL-17RB, social behavior assays, neuronal cell-type-specific expression analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor expression mapping plus genetic deletion with behavioral phenotype, novel neuroimmune function, single study\",\n      \"pmids\": [\"40199322\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-25 (IL-17E) is a cytokine of the IL-17 family produced predominantly by epithelial tuft cells that signals through a heterodimeric receptor composed of IL-17RA and IL-17RB; receptor engagement activates NF-κB via TRAF6, MAPK cascades (ERK, JNK, p38), and a novel Act1-independent STAT5 branch (requiring specific IL-17RB tyrosines), with TRAF4-SMURF2-mediated DAZAP2 degradation enabling ACT1 recruitment; downstream, IL-25 drives type 2 immunity by inducing IL-4, IL-5, IL-13, and IL-9 from ILC2s, MPPtype2 progenitors, Th2 cells, and Th9 cells, while also promoting M2 macrophage polarization via AMPK-mitophagy signaling, suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23/IL-1β/IL-6, stimulating angiogenesis via endothelial PI3K/Akt and ERK/MAPK-VEGF signaling, promoting keratinocyte proliferation and motility, and mediating innate skin inflammation through macrophage p38-dependent neutrophil recruitment; in the intestine, tuft-cell-derived IL-25 forms a feed-forward circuit with ILC2-derived IL-13 to drive goblet and tuft cell differentiation, and IL-25 also functions as a neuromodulatory signal in cortical neurons regulating social behavior through IL-17RB.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-25 (IL-17E) is an epithelial- and tuft-cell-derived cytokine of the IL-17 family that serves as a master initiator of type 2 immunity, signaling through the receptor IL-17RB (IL-17BR/EVI27) to drive IL-4, IL-5, and IL-13 production, eosinophilia, IgE responses, and barrier-tissue inflammation [#0, #1, #25]. Receptor engagement activates NF-κB via constitutively associated TRAF6 and parallel ERK/JNK/p38 MAPK cascades to induce proinflammatory chemokines and Th2-skewing genes [#0, #5]; ACT1 recruitment to IL-17RB requires TRAF4, which directs SMURF2-mediated degradation of the inhibitor DAZAP2, while a distinct set of IL-17RB tyrosines supports a parallel Act1-independent STAT5 branch essential for Th2 polarization [#26, #27]. IL-25 acts on a range of innate effectors—ILC2s, multipotent MPPtype2 progenitors, Th2 and Th9 cells—to amplify type 2 cytokines, with ILC2-derived IL-13 sufficient to drive airway hyperresponsiveness, fibrosis, and epithelial remodeling [#14, #15, #21, #22, #25]. In the intestine, tuft-cell-derived IL-25 establishes a feed-forward circuit with ILC2-derived IL-13 that drives tuft and goblet cell differentiation and anti-helminth immunity [#25]. Beyond type 2 immunity, IL-25 restrains Th17 responses by inducing IL-13 that suppresses dendritic-cell IL-23/IL-1β/IL-6, defining an IL-25–IL-23–IL-17 axis shaped by commensal microbiota [#9, #12]; it also promotes M2 macrophage polarization, keratinocyte proliferation and motility, endothelial angiogenesis via VEGF, and innate skin inflammation through macrophage p38-dependent neutrophil recruitment [#19, #29, #31, #32]. Epithelial IL-25 production is itself gated by mTOR-suppressed autophagy and modulated by IL-22 and protease allergens [#16, #20, #34]. A recent finding extends IL-25 to neuromodulation, where cortical-neuron-derived IL-17E acts on IL-17RB-expressing cortical neurons to regulate social behavior [#36].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that IL-25 is a functional ligand for IL-17RB that triggers NF-κB and chemokine output defined its molecular identity as a signaling cytokine.\",\n      \"evidence\": \"Receptor-ligand binding, NF-κB reporter, and IL-8 production assays in vitro\",\n      \"pmids\": [\"11058597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the second receptor chain or the downstream adaptor\", \"Physiological cellular source not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"In vivo infusion and transgenic overexpression showed IL-25 is sufficient to drive a systemic Th2 cytokine cascade, IgE responses, and eosinophilia, framing it as an initiator of type 2 immunity.\",\n      \"evidence\": \"Cytokine infusion and transgenic mouse models with serum Ig, cytokine, histology, and flow readouts\",\n      \"pmids\": [\"11754819\", \"11714825\", \"12239140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lineage-negative responding cell identity left undefined\", \"Did not resolve direct versus indirect cytokine induction\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic epistasis placed IL-5 and IL-13 (not IL-4 or T cells) as the obligate downstream effectors of IL-25-induced eosinophilia, narrowing the effector arm.\",\n      \"evidence\": \"Adenoviral IL-25 delivery in cytokine- and T-cell-deficient mice with BAL and flow analysis\",\n      \"pmids\": [\"12077275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the gamma-common-dependent innate responder cell not resolved\", \"Did not address receptor signaling mechanism\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying TRAF6 as the constitutively associated adaptor required for IL-25R-driven NF-κB and demonstrating MAPK activation defined the proximal signaling machinery.\",\n      \"evidence\": \"Receptor cross-linking, dominant-negative and TRAF6-deficient MEFs, reciprocal Co-IP, gene expression\",\n      \"pmids\": [\"16393988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of ACT1 and receptor tyrosines not yet defined\", \"Did not address non-NF-κB branches\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that lung fibroblasts and airway smooth muscle constitutively express IL-17BR and respond to IL-25 with chemokine and ECM gene induction, with receptor levels tuned by TNF-α and IFN-γ, extended IL-25 action to structural cells.\",\n      \"evidence\": \"Primary fibroblast and airway smooth muscle cultures, pharmacological pathway inhibitors, PCR/ELISA\",\n      \"pmids\": [\"16522458\", \"16428271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"In vivo relevance of ECM induction not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"STAT6- and CD4-dependent epistasis plus discovery that IL-25 suppresses Th17 responses via IL-13-mediated inhibition of dendritic-cell IL-23 revealed IL-25 as both a type 2 amplifier and a Th17 brake.\",\n      \"evidence\": \"STAT6 KO, CD4 depletion, transgenic and IL-25 KO mice in airway and EAE models with DC stimulation assays\",\n      \"pmids\": [\"17177681\", \"16950278\", \"17200411\", \"17719653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-level basis of STAT6 engagement not defined\", \"Cell-type source of protective IL-25 in EAE unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Commensal-dependent suppression of epithelial IL-25 in the gut defined an IL-25–IL-23–IL-17 regulatory axis tuned by microbiota, situating IL-25 in intestinal immune homeostasis.\",\n      \"evidence\": \"Germ-free mouse model with epithelial sorting, cytokine quantification, T-cell flow cytometry\",\n      \"pmids\": [\"18762568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor linking microbiota to IL-25 repression unknown\", \"Macrophage-IL-23 step not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that IL-25 expands MPPtype2 progenitors and couples to IL-17RB on Th9 cells to drive IL-9 broadened the cellular targets of IL-25 beyond classical Th2 cells.\",\n      \"evidence\": \"Flow cytometry, adoptive transfer into Il25-/- mice, retroviral/transgenic IL-17RB overexpression, helminth and airway models\",\n      \"pmids\": [\"20200520\", \"20154671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between MPPtype2 and ILC2 not yet resolved\", \"Signaling basis of IL-9 induction unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying protease-allergen activation of ERK/p38 as the trigger for epithelial IL-25 induction connected environmental sensing to IL-25 output.\",\n      \"evidence\": \"Lung epithelial cell stimulation with protease-inactivation controls and MAPK inhibitors plus in vivo BAL\",\n      \"pmids\": [\"20514301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease receptor/sensor not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that IL-25-activated ILC2-derived IL-13 is sufficient to drive fibrosis independent of T cells, and that IL-25 preferentially drives MPPtype2 over ILC2 responses, refined the innate effector hierarchy.\",\n      \"evidence\": \"IL-25 administration in Rag-/- and RORα-deficient mice, genome-wide profiling, adoptive transfer after ILC2 depletion\",\n      \"pmids\": [\"24344271\", \"23960191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of ILC2 versus MPPtype2 preference unclear\", \"Receptor signaling distinguishing the two not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Receptor blockade and IL-25 neutralization in rhinovirus models established IL-25 as a driver of viral exacerbation of type 2 airway inflammation, including an age-dependent ILC2 response.\",\n      \"evidence\": \"Murine RV infection with IL-17RB blockade or anti-IL-25, cell recruitment and ILC2 flow cytometry\",\n      \"pmids\": [\"25273095\", \"24910174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RV induces epithelial IL-25 not fully defined\", \"Human translation not directly tested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the tuft-cell origin of IL-25 and the tuft–ILC2–IL-13 feed-forward circuit established the cellular architecture of intestinal type 2 epithelial remodeling.\",\n      \"evidence\": \"Tuft-cell IL-25 expression, helminth infection, IL-13 neutralization, epithelial progenitor differentiation assays\",\n      \"pmids\": [\"26675736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tuft cell sensing input upstream of IL-25 not defined here\", \"Receptor signaling in ILC2 not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying the TRAF4-SMURF2-DAZAP2 axis enabling ACT1 recruitment and a parallel Act1-independent STAT5 branch through specific IL-17RB tyrosines resolved the bifurcated proximal signaling of IL-25.\",\n      \"evidence\": \"Traf4-/- and STAT5 conditional KO mice, Co-IP of TRAF4/SMURF2/DAZAP2, IL-17RB tyrosine mutagenesis, Th2 polarization assays\",\n      \"pmids\": [\"25681341\", \"25821217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of tyrosine-specific STAT5 recruitment unresolved\", \"Cell-type specificity of the two branches not fully mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating receptor-mediated clathrin-dependent uptake of IL-25 by M2 macrophages, and selective caspase-driven apoptosis in IL-17RB-high breast cancer cells, expanded IL-25 biology to non-canonical receptor responses and tumor contexts.\",\n      \"evidence\": \"Psoriatic biopsy IHC, macrophage polarization and endocytosis assays, 3D breast cancer cultures with caspase assays\",\n      \"pmids\": [\"27329229\", \"21490275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling downstream of endocytosed IL-25 not defined\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking IL-25-driven M2 polarization to AMPK activation and PINK1-dependent mitophagy provided a metabolic mechanism for macrophage reprogramming.\",\n      \"evidence\": \"THP-1 monocytes with mitochondrial complex assays, AMPK/mitophagy Western blots, PINK1 knockdown, CCL-22 ELISA\",\n      \"pmids\": [\"35008429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-to-AMPK coupling not defined\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic and neutralization studies established IL-25 as a driver of innate skin inflammation, keratinocyte proliferation/motility, angiogenesis, and Th17-mediated contact hypersensitivity via diverse effector mechanisms.\",\n      \"evidence\": \"Il17e-/- mice, neutralization in imiquimod/tape-stripping and CHS models, macrophage-neutrophil co-culture with p38 inhibition, HUVEC angiogenesis, keratinocyte cultures\",\n      \"pmids\": [\"30738055\", \"29522843\", \"31958433\", \"21205894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor signaling underlying keratinocyte and endothelial responses not fully mapped\", \"Context determining type 2 versus type 17 output unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining keratinocyte-derived IL-25 as an ILC2-activating trigger of allergic skin inflammation, and showing mTOR-suppressed autophagy gates epithelial IL-25 production, connected barrier IL-25 output to upstream regulation and downstream type 2 pathology.\",\n      \"evidence\": \"Cell-type-specific IL-25/IL-17RB conditional KO and IL-13 reporter mice; airway MTOR-KD and Lc3b-/- mice with IL-25 blockade\",\n      \"pmids\": [\"32179159\", \"33077617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal linking autophagy to IL-25 transcription/secretion not defined\", \"Acute versus chronic IL-13 source switch mechanism unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that tuft-cell cysteinyl leukotrienes and IL-25 synergistically activate ILC2s and dendritic cells revealed combinatorial epithelial signals shaping type 2 lung inflammation.\",\n      \"evidence\": \"Tuft-cell-specific Ltc4s deletion, IL-25 blockade, CysLT receptor pharmacology, LTC4 plus subthreshold IL-25 co-administration\",\n      \"pmids\": [\"34932383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of LTC4/IL-25 synergy at the ILC2 level not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying cortical-neuron-derived IL-25 acting on IL-17RB-expressing cortical neurons to regulate social behavior extended IL-25 into neuromodulation beyond immunity.\",\n      \"evidence\": \"Brain-wide receptor mapping, genetic IL-17RB deletion, social behavior assays\",\n      \"pmids\": [\"40199322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal signaling pathway downstream of IL-17RB not defined\", \"Single-study novel function awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct IL-17RB tyrosine-coupled branches (TRAF6/ACT1 NF-κB versus STAT5) are differentially deployed across cell types, and how upstream sensors gate IL-25 release in epithelial, neuronal, and tumor contexts, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the ligand-receptor-adaptor assembly\", \"Cell-type logic of branch selection unresolved\", \"Sensor coupling autophagy/protease/microbiota to IL-25 transcription incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 12, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 26, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL17RB\", \"IL17RA\", \"TRAF6\", \"TRAF4\", \"SMURF2\", \"DAZAP2\", \"ACT1\", \"STAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}