{"gene":"CCL26","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"CCL26 (eotaxin-3) is a functional agonist ligand for CCR3; recombinant CCL26 induced calcium mobilization in CCR3-expressing L1.2 cells (EC50 ~3 nM), competed with 125I-eotaxin for CCR3 binding (IC50 ~13 nM), and was chemotactic for peripheral blood eosinophils and basophils.","method":"Calcium mobilization assay, radioligand competition binding, chemotaxis assay using recombinant protein from baculovirus expression system","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted recombinant protein, multiple orthogonal functional assays (calcium flux, binding competition, chemotaxis)","pmids":["10488147"],"is_preprint":false},{"year":2001,"finding":"The 3D solution structure of CCL26 was determined by NMR; it is monomeric and adopts the canonical chemokine fold (unstructured N-terminus, N-loop, 310-helix, three-stranded antiparallel β-sheet, C-terminal α-helix). Backbone dynamics revealed large-amplitude motions in the N-terminus, N-loop, and β1-β2 turn, suggesting these regions contribute to receptor binding and activation.","method":"NMR spectroscopy (structure determination + 15N relaxation backbone dynamics)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution NMR structure with functional dynamics analysis in a dedicated structural study","pmids":["11425309"],"is_preprint":false},{"year":2001,"finding":"CCL26 is expressed as mRNA in human dermal fibroblasts constitutively and is upregulated by IL-4 and IL-4 + TNF-α; at equimolar concentrations CCL26 showed the same efficacy as eotaxin and eotaxin-2 for eosinophil chemotaxis and actin polymerization (cytoskeletal rearrangement via CCR3/Gi), but lower efficacy for release of toxic reactive oxygen species.","method":"LightCycler RT-PCR, chemotaxis assay (Boyden chamber), actin polymerization assay, ROS release assay, calcium flux assay","journal":"The Journal of Investigative Dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab study","pmids":["11286614"],"is_preprint":false},{"year":2002,"finding":"CCL26 mRNA expression in human lung epithelial cells and dermal fibroblasts is induced by IL-4 and IL-13 in a time- and dose-dependent manner; IL-4 shows ~100-fold greater potency than IL-13. TNF-α alone does not induce CCL26 but synergizes with IL-4/IL-13. Dexamethasone pre-treatment diminishes induction.","method":"Northern blot hybridization","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single method (Northern blot) but multiple cytokine conditions tested systematically in two primary cell types","pmids":["12061839"],"is_preprint":false},{"year":2002,"finding":"CCL26 directly stimulates superoxide anion generation and degranulation (eosinophil peroxidase release) in eosinophil-like HL-60 cells via CCR3; these responses are blocked by anti-CCL26 antibody or anti-CCR3 antibody pre-treatment.","method":"Superoxide anion assay, eosinophil peroxidase degranulation assay, neutralizing antibody blockade","journal":"Experimental Biology and Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with receptor-blocking controls in single lab","pmids":["12192108"],"is_preprint":false},{"year":2003,"finding":"CCL26 binds to CCR2 on monocytes and CCR2-transfected cells but, unlike CCL2/MCP-1, does not trigger intracellular calcium mobilization, enzyme release, or ERK phosphorylation; instead it inhibits CCL2-mediated responses, acting as a natural CCR2 antagonist. CCL26 also promoted active repulsion (chemorepulsion) of monocytes away from a CCL26 gradient, an effect amplified by a co-gradient of CCL2 and abolished by pertussis toxin (Gi-dependent). CCL26 was expressed by vascular endothelial cells and was essential for eosinophil transendothelial migration.","method":"Calcium mobilization assay, enzyme release assay, ERK phosphorylation (Western blot), chemotaxis/chemorepulsion assay (Boyden chamber), pertussis toxin blockade, transfected cell lines","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal assays (signaling, chemotaxis, repulsion, mechanistic blockade) in a single rigorous study","pmids":["12689946"],"is_preprint":false},{"year":2003,"finding":"CCL26 is produced by bronchial epithelial cells, and its production is upregulated by IL-4 and IL-13 and attenuated by IFN-γ and glucocorticoids, paralleling regulation of eotaxin-1 but with distinct kinetics.","method":"Immunohistochemistry (tissue), ELISA (cell culture supernatants), in vitro cytokine stimulation","journal":"Cellular Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ELISA and IHC with multiple cytokine conditions, single lab","pmids":["14698143"],"is_preprint":false},{"year":2004,"finding":"CCL26 acts as a natural antagonist for CCR1 and CCR5: it binds CCR1- and CCR5-transfected cells and to monocytes expressing both receptors, and inhibits chemotaxis, calcium release, and actin polymerization induced by known CCR1/CCR5 agonists. 3D structural analysis identified two distinct epitopes potentially responsible for binding CCR1, CCR2, CCR3, and CCR5.","method":"Radioligand binding (transfected cells), chemotaxis assay, calcium mobilization assay, actin polymerization assay, structural analysis of 3D model","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal functional assays plus structural epitope analysis in a single rigorous study","pmids":["15039444"],"is_preprint":false},{"year":2004,"finding":"IL-4-induced CCL26 production in human lung fibroblasts (HFL-1) is regulated by the STAT6 and MEK/ERK pathways; eotaxin-3/CCL26 production is inhibited by MEK inhibitors (PD98059, U0126) and the p38 MAPK inhibitor SB203580, and is less sensitive to NF-κB inhibition than eotaxin-1 production.","method":"ELISA, RT-PCR, kinase inhibitor treatment (MEK, p38, NF-κB pathway inhibitors)","journal":"Biological & Pharmaceutical Bulletin","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitors with multiple pathway targets, ELISA and RT-PCR, single lab","pmids":["16755001"],"is_preprint":false},{"year":2004,"finding":"IL-4-induced CCL26 production in bronchial epithelial cells (BEAS-2B) is mediated through STAT6 signaling downstream of the type 2 IL-4 receptor; NF-κB inhibition enhanced (rather than inhibited) CCL26 gene expression, in contrast to eotaxin-1.","method":"ELISA, RT-PCR, flow cytometry (receptor expression), Western blot (STAT6 phosphorylation), NF-κB inhibitor treatment","journal":"Annals of Allergy, Asthma & Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods including signaling readouts, single lab","pmids":["15521376"],"is_preprint":false},{"year":2004,"finding":"Concurrent IFN-γ treatment inhibits Th2 cytokine-induced CCL26 production in bronchial epithelial cells by downregulating STAT6 activation; however, 2-day pre-treatment with IFN-γ paradoxically enhances IL-4/IL-13-induced CCL26 production by upregulating IL-4Rα and IL-2Rγ expression.","method":"ELISA, RT-PCR, Western blot (STAT6 phosphorylation), dose/time-dependent cytokine treatment","journal":"American Journal of Respiratory Cell and Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic pathway dissection with multiple methods, single lab","pmids":["15231490"],"is_preprint":false},{"year":2005,"finding":"IL-4 induces CCL26 production in human keratinocytes (HaCaT cells) via the JAK1/JAK2–STAT6 pathway; the proximal STAT6-binding site in the CCL26 promoter is the key response element. TNF-α synergizes with IL-4. Dexamethasone, IFN-γ, p38 MAPK inhibitor (SB202190), leflunomide, and JAK inhibitor 1 (but not JAK3 inhibitor) suppress IL-4-induced CCL26 production, implicating JAK1/JAK2 and the type 2 IL-4 receptor.","method":"ELISA, RT-PCR, 5′ promoter deletion constructs, site-directed mutagenesis, JAK/STAT inhibitors, dominant-negative studies","journal":"Clinical and Experimental Immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter mutagenesis, dominant-negative STAT studies, multiple pharmacological inhibitors, replicated with signaling readouts in a single rigorous study","pmids":["16045735"],"is_preprint":false},{"year":2005,"finding":"CCL26 expressed on the surface of IL-4-stimulated airway epithelial cells is the critical mediator of eosinophil transepithelial migration via CCR3. Cell surface-bound CCL26 (which is predominantly membrane-associated rather than secreted) was partially glycosaminoglycan-dependent but also protein-dependent. Antibody blockade of CCL26 or CCR3 abolished this transepithelial migration.","method":"In vitro transepithelial chemotaxis assay, antibody blockade, confocal microscopy (surface-bound protein localization)","journal":"European Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstituted transepithelial assay with specific antibody blockade and mechanistic surface-localization studies, single focused paper with multiple methods","pmids":["16983721"],"is_preprint":false},{"year":2005,"finding":"CCL26 produced by alveolar epithelial cells (A549) downregulates CCR3 receptor expression by 30-40% and inhibits IL-4/IL-13-induced CCL26 secretion in an autocrine/autoregulatory loop; a CCR3-specific antagonist (SB-328437) significantly decreased IL-4-dependent CCL26 synthesis and release.","method":"ELISA, CCR3 receptor expression (flow cytometry), cycloheximide/actinomycin D inhibition, CCR3 antagonist treatment, anti-CCR3 pre-treatment","journal":"American Journal of Physiology. Lung Cellular and Molecular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods demonstrating CCR3-mediated autoregulation, single lab","pmids":["15863444"],"is_preprint":false},{"year":2005,"finding":"dsRNA (poly(IC)) transfection into airway epithelial cells enhances subsequent IL-4-induced CCL26 production by upregulating IL-4Rα and IL-2Rγ expression, thereby amplifying IL-4-mediated STAT6 phosphorylation; this was reversed by anti-IL-4Rα antibody.","method":"ELISA, RT-PCR, Western blot (STAT6 phosphorylation), antibody blockade, cycloheximide/dexamethasone treatment","journal":"The European Respiratory Journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods, mechanistic pathway confirmation with antibody blockade, single lab","pmids":["16264039"],"is_preprint":false},{"year":2010,"finding":"CCL26 is a functional agonist for CX3CR1 (the fractalkine receptor): it induced calcium flux and chemotaxis in L1.2 cells expressing human CX3CR1 (but not mouse CX3CR1) and competed with CX3CL1 for CX3CR1 binding. In human PBMCs, CCL26 attracted CD16+ NK cells, CD45RA+CD27-CD8+ T cells, and CD14lowCD16high monocytes via CX3CR1. IL-4-stimulated HUVECs producing CCL26 efficiently induced adhesion of CX3CR1-expressing cells.","method":"Calcium flux assay, chemotaxis assay, radioligand competition binding, intraperitoneal injection model (mouse), flow cytometry, real-time PCR","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal assays (calcium flux, competition binding, in vitro and in vivo chemotaxis) in a single rigorous study","pmids":["20974991"],"is_preprint":false},{"year":2010,"finding":"CCL26 promotes human lung fibroblast migration but does not stimulate proliferation, collagen synthesis, α-smooth muscle actin expression, or TGF-β1 release, in contrast to CCL24 which stimulates fibroblast proliferation and collagen synthesis but not migration.","method":"Thymidine incorporation (proliferation), hydroxyproline incorporation (collagen), Boyden chamber chemotaxis, immunostaining (α-SMA), ELISA (TGF-β1)","journal":"Annals of Allergy, Asthma & Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays with appropriate controls, single lab","pmids":["20143648"],"is_preprint":false},{"year":2010,"finding":"IL-4 induces CCL26 mRNA and protein in human monocytes, monocyte-derived macrophages, and U937 cells via STAT6; TNF-α and IL-1β synergize with IL-4 at a step downstream of STAT6 activation. IFN-γ pre-treatment suppresses IL-4-mediated STAT6 phosphorylation and reduces total STAT6 protein, thereby inhibiting CCL26 expression.","method":"RT-PCR, ELISA, Western blot (STAT6 phosphorylation), cytokine stimulation combinations","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple cytokine conditions with signaling readouts, single lab","pmids":["20059579"],"is_preprint":false},{"year":2011,"finding":"IL-13-induced CCL26 transcription is regulated epigenetically: CBP (CREB-binding protein), a histone acetyltransferase, promotes basal and IL-13-induced CCL26 promoter activity. IL-13 promotes formation of a CBP–STAT6 complex and histone H3 acetylation at the CCL26 promoter. CBP gene silencing decreases IL-13-induced CCL26 transcription; conversely, histone deacetylase inhibition increases it. A CRE site in the CCL26 promoter is required for IL-13-induced activity.","method":"Promoter-reporter assays, ChIP (histone acetylation, CBP, STAT6 occupancy), siRNA knockdown, HDAC inhibitor treatment","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter-reporter, ChIP, siRNA knockdown with multiple orthogonal readouts in a single rigorous study","pmids":["21325281"],"is_preprint":false},{"year":2012,"finding":"IL-4 regulates CCL26 in keratinocytes via JAK1/JAK2–STAT6; serial 5′ promoter deletion and mutagenesis identified the proximal STAT6 site as the key response element; IL-4 activates STAT6 (not STAT3) and induces its nuclear translocation; JAK inhibitors suppress CCL26 upregulation in a dose-dependent manner.","method":"RT-PCR, ELISA, promoter-reporter assay, 5′ deletion series, site-directed mutagenesis, dominant-negative STAT studies, JAK inhibitors, Western blot (STAT3/6 phosphorylation), nuclear translocation assay","journal":"Molecular Immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis, dominant-negative studies, nuclear translocation, multiple signaling inhibitors in one rigorous study","pmids":["22226123"],"is_preprint":false},{"year":2012,"finding":"Omeprazole (and lansoprazole) blocks IL-4-stimulated CCL26 promoter activation and secretion in EoE esophageal epithelial cells by preventing nuclear binding of STAT6, RNA polymerase II, and trimethylated H3K4 to the endogenous CCL26 promoter, without affecting STAT6 phosphorylation or nuclear translocation, and without affecting CCL26 mRNA stability.","method":"ELISA, RT-PCR, Western blot (STAT6 phosphorylation/translocation), promoter-reporter construct, ChIP (STAT6, RNA Pol II, H3K4me3)","journal":"PloS One","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP assays plus promoter reporter plus protein-level readouts, mechanistic dissection with multiple orthogonal approaches in a single rigorous study","pmids":["23185525"],"is_preprint":false},{"year":2013,"finding":"DNA demethylation of a specific CpG site (CpG 2) in the CCL26 promoter, juxtaposed to a CRE site, is associated with elevated basal and IL-13-induced CCL26 expression in allergic tissue-derived epithelial cells; CpG 2 methylation inversely correlates with CCL26 expression. EMSA demonstrated that CREB-binding protein and ATF-2 binding to the CRE site is methylation-dependent. 5-Azacytidine treatment promotes CCL26 production.","method":"Bisulfite sequencing, promoter-reporter assay (methylation-free in vitro system), 5-azacytidine treatment, EMSA","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — EMSA, methylation-free promoter reconstitution, bisulfite sequencing, and pharmacological validation in one study","pmids":["24323578"],"is_preprint":false},{"year":2013,"finding":"CCL26 binds to CX3CR1 on NK cells and promotes F-actin reorganization and NK cell chemotaxis via a tyrosine kinase-sensitive pathway (genistein-sensitive); a single antigen nasal provocation challenge increases CX3CR1 expression on NK cells in allergic rhinitis patients, augmenting NK cell chemotaxis toward CCL26.","method":"Microchemotaxis chambers, flow cytometry, confocal microscopy (F-actin), genistein (tyrosine kinase inhibitor) blockade","journal":"Clinical and Experimental Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional chemotaxis with mechanistic inhibitor and cytoskeletal readout, single lab","pmids":["23414540"],"is_preprint":false},{"year":2013,"finding":"CCL26 expression in colonic myofibroblasts is induced by IL-4 and IL-13 via STAT6; IFN-γ acts as a negative regulator via STAT1 activation. SOCS1 is also implicated as a regulatory component of the pathway.","method":"RT-PCR, ELISA, Western blot (STAT6/STAT1 signaling), cytokine stimulation","journal":"Clinical and Experimental Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple signaling readouts and cytokine conditions, single lab","pmids":["23607908"],"is_preprint":false},{"year":2013,"finding":"CCL26 stimulates migration, invasion, and MMP2 activity of extravillous trophoblast-derived HTR8/SVneo cells, and increases cell adhesion to collagen IV and fibronectin; no effect on TIMP2 activity.","method":"xCELLigence real-time cell migration, wound-healing assay, Matrigel invasion assay, zymography (MMP2), reverse zymography (TIMP2), adhesion assay","journal":"Human Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays with recombinant CCL26, single lab and single cell line model","pmids":["23477905"],"is_preprint":false},{"year":2015,"finding":"CCL26 exhibits direct bactericidal activity against airway pathogens (S. pneumoniae, S. aureus, H. influenzae, P. aeruginosa) via membrane disruption; the cationic/amphipathic COOH-terminal region is responsible for bactericidal activity. Mast cell chymase and tryptase cleave CCL26 to generate distinct fragments: the COOH-terminal fragment retains antibacterial activity, the NH2-terminal fragment has potent LPS-neutralizing activity, and neither fragment activates CCR3.","method":"Viable count assay, electron microscopy, bacterial membrane permeabilization assay, protease cleavage (chymase, tryptase), LPS neutralization assay, CCR3 activation assay","journal":"Allergy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal mechanistic assays (bactericidal, membrane disruption, fragment characterization, receptor activation) in a single rigorous study","pmids":["25377782"],"is_preprint":false},{"year":2015,"finding":"JAK-STAT6 pathway inhibitors (AS1517499, leflunomide, ruxolitinib) block Th2 cytokine-stimulated CCL26 expression in esophageal fibroblasts and epithelial cells by inhibiting STAT6 phosphorylation and nuclear translocation. Omeprazole does not inhibit cytokine-stimulated CCL26 expression in esophageal fibroblasts (negative result for omeprazole in fibroblasts vs. positive in epithelial cells).","method":"ELISA, Western blot (STAT6 phosphorylation/translocation), JAK-STAT inhibitor treatment, nuclear translocation assay","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors, multiple cell types, signaling and secretion readouts, single lab","pmids":["27310888"],"is_preprint":false},{"year":2016,"finding":"IL-13-induced CCL26 expression in airway epithelial cells is mediated through a nongastric H,K-ATPase (encoded by ATP12A): knockdown of ATP12A significantly attenuates IL-13-induced CCL26 expression. PPIs block IL-13-enhanced H+/K+ exchange (detected by intracellular pH imaging) and CCL26 expression, and also accelerate IL-13-induced CCL26 mRNA decay.","method":"ELISA, Western blot, RT-PCR, intracellular pH imaging, siRNA knockdown (ATP12A), H,K-ATPase inhibitor (SCH-28080), extracellular K+ manipulation","journal":"The Journal of Allergy and Clinical Immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — siRNA knockdown with mechanistic rescue (pH imaging, K+ manipulation), multiple orthogonal readouts in a single rigorous study","pmids":["27717558"],"is_preprint":false},{"year":2018,"finding":"CISH (a SOCS family member) is a negative regulator of IL-13-induced CCL26 production in human lung fibroblasts; CISH is itself induced by IL-13 via STAT6 phosphorylation. Loss-of-function (siRNA) increases CCL26, and gain-of-function (overexpression) decreases IL-13-induced CCL26 expression.","method":"cDNA microarray, quantitative RT-PCR, ELISA, Western blot, siRNA knockdown, vector overexpression","journal":"Allergology International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function in primary cells, multiple readouts, single lab","pmids":["30197185"],"is_preprint":false},{"year":2019,"finding":"15-Lipoxygenase 1 (15LO1) promotes CCL26 expression in nasal epithelial cells via ERK activation: 15LO1 knockdown (DsiRNA) and enzymatic inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression; ERK inhibition alone also decreased IL-13-induced CCL26.","method":"Quantitative RT-PCR, Western blot (15LO1, CCL26, phospho-ERK), ELISA, ALOX15 DsiRNA knockdown, specific 15LO1 inhibitor, ERK inhibitors, air-liquid interface culture","journal":"The Journal of Allergy and Clinical Immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — siRNA knockdown + enzymatic inhibitor + pathway inhibitor with multiple orthogonal readouts in primary cells","pmids":["31301373"],"is_preprint":false},{"year":2021,"finding":"IL-4-stimulated CCL26 secretion in EoE esophageal squamous cells requires a nongastric H,K-ATPase (ngH+,K+ATPase; ATP12A) and intracellular calcium: IL-4 increases calcium via endoplasmic reticulum release (blocked by 2-APB) and L-type calcium channel entry (blocked by verapamil and diltiazem); chelation of intracellular calcium (EGTA-AM) blocks CCL26 secretion. Omeprazole and SCH-28080 also block IL-4-induced CCL26 secretion. Combined omeprazole + verapamil suppressed CCL26 more than either alone.","method":"ELISA, qRT-PCR, Western blot, Fluo-4 fluorescence (intracellular calcium), pharmacological inhibitors (omeprazole, SCH-28080, EGTA-AM, 2-APB, verapamil, diltiazem), primary EoE cells, RNA-seq validation","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple pharmacological dissections of distinct calcium pathways plus ngH+,K+ATPase, validated in primary cells and RNA-seq datasets","pmids":["33581123"],"is_preprint":false},{"year":2023,"finding":"Airway epithelial cell-derived CCL26 activates CX3CR1+ alveolar macrophages via CCL26–CX3CR1 receptor-ligand interaction, inducing these macrophages to secrete C1q which facilitates eosinophil clearance, thereby resolving allergic lung eosinophilia. Conditional knockout of CCL26 in airway epithelial cells or depletion of CX3CR1 macrophages both delayed resolution with prolonged tissue eosinophilia.","method":"Mass cytometry, single-cell RNA sequencing, conditional CCL26 knockout mice, CX3CR1 macrophage depletion, biophysical binding assays, allergen bronchoprovocation (human), immunological assays","journal":"American Journal of Respiratory and Critical Care Medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional knockout, cell depletion, receptor-ligand binding, scRNA-seq, human and mouse validation across multiple orthogonal approaches","pmids":["36790376"],"is_preprint":false},{"year":2011,"finding":"CCL26 promoter activation by IL-13 requires the CRE site; the STAT6 pathway drives CCL26 expression but a CBP–STAT6 complex formation and subsequent histone H3 acetylation at the CCL26 promoter locus are mechanistically required for full transcriptional output.","method":"ChIP (CBP, STAT6, acetylated H3), promoter-reporter, CBP siRNA, HDAC inhibitor","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP plus promoter-reporter plus siRNA knockdown with multiple readouts in one study (same paper as PMID 21325281, listed separately above for epigenetic mechanism)","pmids":["21325281"],"is_preprint":false},{"year":2011,"finding":"STAT6 phosphorylation inhibitors directly bind STAT6 and prevent its active dimer formation, blocking CCL26 secretion by bronchial epithelial cells stimulated with IL-4.","method":"Small molecule STAT6 inhibitor (compound R-84), ELISA (CCL26 secretion), STAT6 phosphorylation assay","journal":"Bioorganic & Medicinal Chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitor with direct binding claim and functional readout, single lab single method","pmids":["22217933"],"is_preprint":false},{"year":2012,"finding":"LTD4 potentiates IL-13-induced CCL26 release by airway epithelial cells via CysLT1 receptor upregulation; IL-13 first upregulates CysLT1 expression, increasing cellular responsiveness to LTD4 which then amplifies CCL26 secretion. LTD4 alone weakly induced CCL26; it had no effect on IL-4-stimulated cells.","method":"ELISA, RT-PCR, flow cytometry (CysLT1 expression), time-course stimulation","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ELISA and receptor expression with mechanistic ordering of pathway events, single lab","pmids":["22952702"],"is_preprint":false},{"year":2017,"finding":"PRL-3 (phosphatase of regenerating liver-3) upregulates CCL26 expression in colorectal cancer cells; CCL26 then binds CCR3 on tumor-associated macrophages (TAMs), mobilizing intracellular Ca2+ in TAMs and increasing IL-6 and IL-8 expression, which enhances colorectal cancer cell invasiveness.","method":"Gene ontology analysis, IHC (PRL-3, CCL26, CCR3), CCR3-CCL26 binding/co-culture assay, intracellular Ca2+ mobilization assay, Matrigel invasion assay, in vivo mouse injection model","journal":"Molecular Cancer Therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-mediated calcium signaling, co-culture invasion assay, in vivo validation, single lab","pmids":["29051319"],"is_preprint":false},{"year":2021,"finding":"CCL26 promotes pancreatic cancer cell invasion via activation of the PI3K/AKT/mTOR pathway: recombinant CCL26 treatment of PDAC cell lines increased phosphorylation of PI3K, AKT, and mTOR, and enhanced invasiveness in Matrigel transwell assays.","method":"Transwell migration/invasion assay, Western blot (p-PI3K, p-AKT, p-mTOR), RT-qPCR, IHC, recombinant CCL26 treatment","journal":"Acta Biochimica et Biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — recombinant protein treatment with signaling readouts and functional invasion assay, single lab","pmids":["33764366"],"is_preprint":false}],"current_model":"CCL26 (eotaxin-3) is a secreted CC chemokine that functions as a selective CCR3 agonist recruiting eosinophils, basophils, and Th2 lymphocytes, and additionally acts as a functional agonist for CX3CR1 (recruiting NK cells and monocytes) while serving as a natural antagonist for CCR1, CCR2, and CCR5; its expression is induced by IL-4 and IL-13 predominantly via the JAK1/2–STAT6 pathway (with epigenetic amplification through CBP-mediated H3 acetylation and promoter demethylation) in epithelial cells, fibroblasts, keratinocytes, and monocytes, and is mechanistically controlled by a nongastric H+,K+-ATPase (ATP12A) and intracellular calcium signaling; on the cell surface it mediates eosinophil transepithelial migration in a membrane-bound form, and in the airway it drives eosinophil resolution via CCL26–CX3CR1-mediated activation of CX3CR1+ macrophages to secrete C1q."},"narrative":{"mechanistic_narrative":"CCL26 (eotaxin-3) is a secreted CC chemokine that orchestrates Th2-type leukocyte trafficking and resolution by engaging multiple chemokine receptors with opposing functional outcomes [PMID:10488147, PMID:20974991]. It is a high-affinity functional agonist of CCR3, mobilizing calcium, driving actin polymerization, and chemoattracting eosinophils and basophils [PMID:10488147, PMID:11286614], and it additionally acts as a functional agonist of the fractalkine receptor CX3CR1, recruiting CD16+ NK cells, effector CD8+ T cells, and CD14low CD16high monocytes [PMID:20974991, PMID:23414540]. In parallel, CCL26 binds CCR1, CCR2, and CCR5 without activating them and instead behaves as a natural antagonist that suppresses responses to their cognate agonists and can drive Gi-dependent chemorepulsion of monocytes [PMID:12689946, PMID:15039444]. Beyond receptor signaling, CCL26 has direct bactericidal activity against airway pathogens through its cationic, amphipathic C-terminus, and mast-cell chymase/tryptase cleavage separates an antibacterial C-terminal fragment from an LPS-neutralizing N-terminal fragment [PMID:25377782]. CCL26 expression is induced by the Th2 cytokines IL-4 and IL-13 through the JAK1/JAK2–STAT6 axis acting on a proximal STAT6 promoter element, with full transcriptional output requiring CBP–STAT6 complex formation, histone H3 acetylation, and promoter CpG demethylation adjacent to a CRE site [PMID:16045735, PMID:22226123, PMID:21325281, PMID:24323578]. Its induction is further gated by a nongastric H+,K+-ATPase (ATP12A) and intracellular calcium signaling, which is why proton-pump inhibitors block CCL26 in epithelial cells [PMID:27717558, PMID:33581123, PMID:23185525]. Functionally, surface-bound CCL26 on IL-4-stimulated airway epithelium mediates eosinophil transepithelial migration via CCR3 [PMID:16983721], while epithelial CCL26 also drives resolution of allergic eosinophilia by activating CX3CR1+ macrophages to secrete C1q and clear eosinophils [PMID:36790376]. CCL26 additionally promotes migration and invasion of non-immune cells including fibroblasts, trophoblasts, and tumor cells [PMID:20143648, PMID:23477905, PMID:29051319].","teleology":[{"year":1999,"claim":"Established CCL26 as a bona fide functional chemokine by showing it is an agonist of CCR3, defining its primary receptor and eosinophil/basophil-recruiting role.","evidence":"Calcium flux, radioligand competition binding, and chemotaxis with recombinant baculovirus-expressed protein on CCR3+ cells and primary leukocytes","pmids":["10488147"],"confidence":"High","gaps":["No structural basis for receptor selectivity addressed","In vivo relevance not yet tested"]},{"year":2001,"claim":"Defined the 3D fold and dynamics of CCL26, linking flexible N-terminal/N-loop regions to receptor binding and activation.","evidence":"NMR structure determination with 15N relaxation backbone dynamics","pmids":["11425309"],"confidence":"High","gaps":["No co-structure with any receptor","Functional consequences of dynamic regions inferred, not mutated"]},{"year":2001,"claim":"Showed CCL26 is constitutively and IL-4-inducibly expressed by dermal fibroblasts and is equipotent with other eotaxins for chemotaxis but weaker for ROS release, hinting at signaling biases.","evidence":"RT-PCR, chemotaxis, actin polymerization, ROS, and calcium assays in primary fibroblasts","pmids":["11286614"],"confidence":"Medium","gaps":["Mechanism of reduced ROS efficacy unexplained","Single cell type"]},{"year":2003,"claim":"Revealed CCL26 as a multi-receptor regulator that antagonizes CCR2 and drives monocyte chemorepulsion, distinguishing it functionally from canonical agonist chemokines.","evidence":"Calcium, ERK, enzyme-release, and chemorepulsion assays with pertussis toxin blockade in transfected cells and monocytes","pmids":["12689946"],"confidence":"High","gaps":["Structural basis of antagonism vs agonism not resolved","In vivo significance of chemorepulsion untested"]},{"year":2004,"claim":"Extended CCL26's antagonist role to CCR1 and CCR5 and mapped distinct structural epitopes for its multiple receptor interactions.","evidence":"Radioligand binding, chemotaxis, calcium, actin assays in transfected cells plus 3D model epitope analysis","pmids":["15039444"],"confidence":"High","gaps":["Epitopes predicted from model, not co-crystallized","No mutational confirmation of epitope assignments"]},{"year":2004,"claim":"Established the JAK–STAT6 and MEK/ERK pathways and a proximal STAT6 promoter element as the core IL-4/IL-13 induction machinery for CCL26, distinguishing its regulation from eotaxin-1.","evidence":"Promoter deletion/mutagenesis, dominant-negative STAT6, JAK/MEK/p38/NF-κB inhibitors, signaling readouts across fibroblasts, epithelium, and keratinocytes","pmids":["16755001","15521376","16045735","15231490"],"confidence":"High","gaps":["Cell-type-specific NF-κB effects unexplained","Quantitative contribution of ERK vs STAT6 unclear"]},{"year":2005,"claim":"Demonstrated that surface-bound CCL26 on IL-4-stimulated epithelium is the operative form driving eosinophil transepithelial migration via CCR3, and that CCL26 autoregulates via CCR3.","evidence":"Transepithelial chemotaxis with antibody blockade, confocal surface localization, CCR3 antagonist and flow cytometry autoregulation studies","pmids":["16983721","15863444"],"confidence":"High","gaps":["Relative contribution of GAG vs protein anchoring not quantified","In vivo membrane-bound role untested"]},{"year":2010,"claim":"Identified CCL26 as a functional CX3CR1 agonist, broadening its target leukocyte repertoire to NK cells, effector T cells, and patrolling monocytes.","evidence":"Calcium flux, competition binding, in vitro and in vivo chemotaxis, HUVEC adhesion assays with human (not mouse) CX3CR1","pmids":["20974991"],"confidence":"High","gaps":["Species selectivity (human vs mouse CX3CR1) mechanistically unexplained","Structural basis of CX3CR1 engagement unknown"]},{"year":2011,"claim":"Defined epigenetic control of CCL26 transcription, showing CBP–STAT6 complex formation, histone H3 acetylation, and a required CRE site for full IL-13-induced output.","evidence":"ChIP, promoter-reporter, CBP siRNA, and HDAC inhibitor assays","pmids":["21325281"],"confidence":"High","gaps":["Stimulus-specific CBP recruitment kinetics not detailed","Interplay with other coactivators unmapped"]},{"year":2013,"claim":"Connected CCL26 expression to promoter DNA methylation, showing CpG demethylation near the CRE site permits CBP/ATF-2 binding and elevated expression in allergic tissue.","evidence":"Bisulfite sequencing, methylation-free promoter reporters, 5-azacytidine treatment, and EMSA","pmids":["24323578"],"confidence":"High","gaps":["Enzymes driving demethylation in allergic tissue unidentified","Causality in patients correlational"]},{"year":2015,"claim":"Uncovered a receptor-independent innate immune function of CCL26 as a direct bactericidal peptide and a protease-cleaved generator of distinct antibacterial and LPS-neutralizing fragments.","evidence":"Viable count, electron microscopy, membrane permeabilization, chymase/tryptase cleavage, LPS neutralization, and CCR3 activation assays","pmids":["25377782"],"confidence":"High","gaps":["In vivo antimicrobial relevance untested","Physiological abundance of cleaved fragments unknown"]},{"year":2016,"claim":"Identified the nongastric H+,K+-ATPase ATP12A and intracellular calcium as required upstream regulators of Th2-cytokine-induced CCL26, explaining proton-pump-inhibitor responsiveness.","evidence":"ATP12A siRNA knockdown, intracellular pH imaging, K+ manipulation, calcium imaging, and PPI/SCH-28080 treatment in epithelial and EoE cells","pmids":["27717558","33581123","23185525"],"confidence":"High","gaps":["Molecular link between H+/K+ exchange and STAT6-driven transcription incomplete","Tissue specificity of PPI effect (epithelium vs fibroblasts) unexplained"]},{"year":2018,"claim":"Mapped negative feedback regulators of CCL26, with CISH and IFN-γ/STAT1 dampening STAT6-driven expression.","evidence":"Microarray, reciprocal siRNA/overexpression of CISH, and STAT1/STAT6 readouts in fibroblasts and myofibroblasts","pmids":["30197185","23607908","20059579"],"confidence":"Medium","gaps":["Relative weight of feedback regulators in vivo unknown","Mechanism of CISH action on STAT6 not detailed"]},{"year":2019,"claim":"Added 15-lipoxygenase-1/ERK as an amplifying input to IL-13-induced CCL26 in nasal epithelium, integrating lipid metabolism into chemokine induction.","evidence":"ALOX15 DsiRNA, enzymatic and ERK inhibitors with phospho-ERK and CCL26 readouts in air-liquid interface cultures","pmids":["31301373"],"confidence":"High","gaps":["15LO1 metabolite linking to ERK not identified","Restricted to nasal epithelium"]},{"year":2023,"claim":"Established an in vivo resolution function for epithelial CCL26, which activates CX3CR1+ macrophages to secrete C1q and clear eosinophils, resolving allergic lung inflammation.","evidence":"Conditional epithelial CCL26 knockout and CX3CR1-macrophage depletion in mice, scRNA-seq, mass cytometry, binding assays, and human bronchoprovocation","pmids":["36790376"],"confidence":"High","gaps":["Mechanism of C1q-mediated eosinophil clearance not fully dissected","Whether membrane-bound vs soluble CCL26 mediates macrophage activation unclear"]},{"year":2021,"claim":"Extended CCL26 function to non-immune migration and tumor biology, promoting fibroblast/trophoblast/tumor cell invasion via CCR3-TAM crosstalk and PI3K/AKT/mTOR signaling.","evidence":"Invasion/migration assays, MMP2 zymography, CCR3 co-culture calcium signaling, PI3K/AKT/mTOR Western blots, and in vivo tumor models","pmids":["20143648","23477905","29051319","33764366"],"confidence":"Medium","gaps":["Receptor mediating tumor-cell-intrinsic PI3K/AKT signaling not defined","In vivo causality for invasion limited to single models"]},{"year":null,"claim":"It remains unresolved how CCL26's structural features dictate the switch between agonism (CCR3, CX3CR1) and antagonism (CCR1/2/5), and how membrane-bound versus soluble forms partition between recruitment and resolution functions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No receptor co-structures","No structure-guided mutants tested across the full receptor panel","Membrane vs soluble functional partitioning undefined in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0090729","term_label":"toxin activity","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005886","term_label":"plasma 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Acts as a ligand for C-C chemokine receptor CCR3 which triggers Ca(2+) mobilization in eosinophils (PubMed:10415065, PubMed:10488147, PubMed:11425309). Also acts as a ligand for CX3C chemokine receptor CX3CR1, inducing cell chemotaxis (PubMed:20974991)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9Y258/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCL26","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCL26","total_profiled":1310},"omim":[{"mim_id":"610247","title":"ESOPHAGITIS, EOSINOPHILIC, 1; EOE1","url":"https://www.omim.org/entry/610247"},{"mim_id":"604697","title":"CHEMOKINE, CC MOTIF, LIGAND 26; CCL26","url":"https://www.omim.org/entry/604697"},{"mim_id":"601470","title":"CHEMOKINE, CX3C MOTIF, RECEPTOR 1; 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mobilization assay, radioligand competition binding, chemotaxis assay using recombinant protein from baculovirus expression system\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted recombinant protein, multiple orthogonal functional assays (calcium flux, binding competition, chemotaxis)\",\n      \"pmids\": [\"10488147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The 3D solution structure of CCL26 was determined by NMR; it is monomeric and adopts the canonical chemokine fold (unstructured N-terminus, N-loop, 310-helix, three-stranded antiparallel β-sheet, C-terminal α-helix). Backbone dynamics revealed large-amplitude motions in the N-terminus, N-loop, and β1-β2 turn, suggesting these regions contribute to receptor binding and activation.\",\n      \"method\": \"NMR spectroscopy (structure determination + 15N relaxation backbone dynamics)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution NMR structure with functional dynamics analysis in a dedicated structural study\",\n      \"pmids\": [\"11425309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CCL26 is expressed as mRNA in human dermal fibroblasts constitutively and is upregulated by IL-4 and IL-4 + TNF-α; at equimolar concentrations CCL26 showed the same efficacy as eotaxin and eotaxin-2 for eosinophil chemotaxis and actin polymerization (cytoskeletal rearrangement via CCR3/Gi), but lower efficacy for release of toxic reactive oxygen species.\",\n      \"method\": \"LightCycler RT-PCR, chemotaxis assay (Boyden chamber), actin polymerization assay, ROS release assay, calcium flux assay\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab study\",\n      \"pmids\": [\"11286614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCL26 mRNA expression in human lung epithelial cells and dermal fibroblasts is induced by IL-4 and IL-13 in a time- and dose-dependent manner; IL-4 shows ~100-fold greater potency than IL-13. TNF-α alone does not induce CCL26 but synergizes with IL-4/IL-13. Dexamethasone pre-treatment diminishes induction.\",\n      \"method\": \"Northern blot hybridization\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single method (Northern blot) but multiple cytokine conditions tested systematically in two primary cell types\",\n      \"pmids\": [\"12061839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCL26 directly stimulates superoxide anion generation and degranulation (eosinophil peroxidase release) in eosinophil-like HL-60 cells via CCR3; these responses are blocked by anti-CCL26 antibody or anti-CCR3 antibody pre-treatment.\",\n      \"method\": \"Superoxide anion assay, eosinophil peroxidase degranulation assay, neutralizing antibody blockade\",\n      \"journal\": \"Experimental Biology and Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with receptor-blocking controls in single lab\",\n      \"pmids\": [\"12192108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL26 binds to CCR2 on monocytes and CCR2-transfected cells but, unlike CCL2/MCP-1, does not trigger intracellular calcium mobilization, enzyme release, or ERK phosphorylation; instead it inhibits CCL2-mediated responses, acting as a natural CCR2 antagonist. CCL26 also promoted active repulsion (chemorepulsion) of monocytes away from a CCL26 gradient, an effect amplified by a co-gradient of CCL2 and abolished by pertussis toxin (Gi-dependent). CCL26 was expressed by vascular endothelial cells and was essential for eosinophil transendothelial migration.\",\n      \"method\": \"Calcium mobilization assay, enzyme release assay, ERK phosphorylation (Western blot), chemotaxis/chemorepulsion assay (Boyden chamber), pertussis toxin blockade, transfected cell lines\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal assays (signaling, chemotaxis, repulsion, mechanistic blockade) in a single rigorous study\",\n      \"pmids\": [\"12689946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL26 is produced by bronchial epithelial cells, and its production is upregulated by IL-4 and IL-13 and attenuated by IFN-γ and glucocorticoids, paralleling regulation of eotaxin-1 but with distinct kinetics.\",\n      \"method\": \"Immunohistochemistry (tissue), ELISA (cell culture supernatants), in vitro cytokine stimulation\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ELISA and IHC with multiple cytokine conditions, single lab\",\n      \"pmids\": [\"14698143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CCL26 acts as a natural antagonist for CCR1 and CCR5: it binds CCR1- and CCR5-transfected cells and to monocytes expressing both receptors, and inhibits chemotaxis, calcium release, and actin polymerization induced by known CCR1/CCR5 agonists. 3D structural analysis identified two distinct epitopes potentially responsible for binding CCR1, CCR2, CCR3, and CCR5.\",\n      \"method\": \"Radioligand binding (transfected cells), chemotaxis assay, calcium mobilization assay, actin polymerization assay, structural analysis of 3D model\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal functional assays plus structural epitope analysis in a single rigorous study\",\n      \"pmids\": [\"15039444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-4-induced CCL26 production in human lung fibroblasts (HFL-1) is regulated by the STAT6 and MEK/ERK pathways; eotaxin-3/CCL26 production is inhibited by MEK inhibitors (PD98059, U0126) and the p38 MAPK inhibitor SB203580, and is less sensitive to NF-κB inhibition than eotaxin-1 production.\",\n      \"method\": \"ELISA, RT-PCR, kinase inhibitor treatment (MEK, p38, NF-κB pathway inhibitors)\",\n      \"journal\": \"Biological & Pharmaceutical Bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitors with multiple pathway targets, ELISA and RT-PCR, single lab\",\n      \"pmids\": [\"16755001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-4-induced CCL26 production in bronchial epithelial cells (BEAS-2B) is mediated through STAT6 signaling downstream of the type 2 IL-4 receptor; NF-κB inhibition enhanced (rather than inhibited) CCL26 gene expression, in contrast to eotaxin-1.\",\n      \"method\": \"ELISA, RT-PCR, flow cytometry (receptor expression), Western blot (STAT6 phosphorylation), NF-κB inhibitor treatment\",\n      \"journal\": \"Annals of Allergy, Asthma & Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods including signaling readouts, single lab\",\n      \"pmids\": [\"15521376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Concurrent IFN-γ treatment inhibits Th2 cytokine-induced CCL26 production in bronchial epithelial cells by downregulating STAT6 activation; however, 2-day pre-treatment with IFN-γ paradoxically enhances IL-4/IL-13-induced CCL26 production by upregulating IL-4Rα and IL-2Rγ expression.\",\n      \"method\": \"ELISA, RT-PCR, Western blot (STAT6 phosphorylation), dose/time-dependent cytokine treatment\",\n      \"journal\": \"American Journal of Respiratory Cell and Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic pathway dissection with multiple methods, single lab\",\n      \"pmids\": [\"15231490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-4 induces CCL26 production in human keratinocytes (HaCaT cells) via the JAK1/JAK2–STAT6 pathway; the proximal STAT6-binding site in the CCL26 promoter is the key response element. TNF-α synergizes with IL-4. Dexamethasone, IFN-γ, p38 MAPK inhibitor (SB202190), leflunomide, and JAK inhibitor 1 (but not JAK3 inhibitor) suppress IL-4-induced CCL26 production, implicating JAK1/JAK2 and the type 2 IL-4 receptor.\",\n      \"method\": \"ELISA, RT-PCR, 5′ promoter deletion constructs, site-directed mutagenesis, JAK/STAT inhibitors, dominant-negative studies\",\n      \"journal\": \"Clinical and Experimental Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter mutagenesis, dominant-negative STAT studies, multiple pharmacological inhibitors, replicated with signaling readouts in a single rigorous study\",\n      \"pmids\": [\"16045735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CCL26 expressed on the surface of IL-4-stimulated airway epithelial cells is the critical mediator of eosinophil transepithelial migration via CCR3. Cell surface-bound CCL26 (which is predominantly membrane-associated rather than secreted) was partially glycosaminoglycan-dependent but also protein-dependent. Antibody blockade of CCL26 or CCR3 abolished this transepithelial migration.\",\n      \"method\": \"In vitro transepithelial chemotaxis assay, antibody blockade, confocal microscopy (surface-bound protein localization)\",\n      \"journal\": \"European Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstituted transepithelial assay with specific antibody blockade and mechanistic surface-localization studies, single focused paper with multiple methods\",\n      \"pmids\": [\"16983721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CCL26 produced by alveolar epithelial cells (A549) downregulates CCR3 receptor expression by 30-40% and inhibits IL-4/IL-13-induced CCL26 secretion in an autocrine/autoregulatory loop; a CCR3-specific antagonist (SB-328437) significantly decreased IL-4-dependent CCL26 synthesis and release.\",\n      \"method\": \"ELISA, CCR3 receptor expression (flow cytometry), cycloheximide/actinomycin D inhibition, CCR3 antagonist treatment, anti-CCR3 pre-treatment\",\n      \"journal\": \"American Journal of Physiology. Lung Cellular and Molecular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods demonstrating CCR3-mediated autoregulation, single lab\",\n      \"pmids\": [\"15863444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"dsRNA (poly(IC)) transfection into airway epithelial cells enhances subsequent IL-4-induced CCL26 production by upregulating IL-4Rα and IL-2Rγ expression, thereby amplifying IL-4-mediated STAT6 phosphorylation; this was reversed by anti-IL-4Rα antibody.\",\n      \"method\": \"ELISA, RT-PCR, Western blot (STAT6 phosphorylation), antibody blockade, cycloheximide/dexamethasone treatment\",\n      \"journal\": \"The European Respiratory Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods, mechanistic pathway confirmation with antibody blockade, single lab\",\n      \"pmids\": [\"16264039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCL26 is a functional agonist for CX3CR1 (the fractalkine receptor): it induced calcium flux and chemotaxis in L1.2 cells expressing human CX3CR1 (but not mouse CX3CR1) and competed with CX3CL1 for CX3CR1 binding. In human PBMCs, CCL26 attracted CD16+ NK cells, CD45RA+CD27-CD8+ T cells, and CD14lowCD16high monocytes via CX3CR1. IL-4-stimulated HUVECs producing CCL26 efficiently induced adhesion of CX3CR1-expressing cells.\",\n      \"method\": \"Calcium flux assay, chemotaxis assay, radioligand competition binding, intraperitoneal injection model (mouse), flow cytometry, real-time PCR\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal assays (calcium flux, competition binding, in vitro and in vivo chemotaxis) in a single rigorous study\",\n      \"pmids\": [\"20974991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCL26 promotes human lung fibroblast migration but does not stimulate proliferation, collagen synthesis, α-smooth muscle actin expression, or TGF-β1 release, in contrast to CCL24 which stimulates fibroblast proliferation and collagen synthesis but not migration.\",\n      \"method\": \"Thymidine incorporation (proliferation), hydroxyproline incorporation (collagen), Boyden chamber chemotaxis, immunostaining (α-SMA), ELISA (TGF-β1)\",\n      \"journal\": \"Annals of Allergy, Asthma & Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays with appropriate controls, single lab\",\n      \"pmids\": [\"20143648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-4 induces CCL26 mRNA and protein in human monocytes, monocyte-derived macrophages, and U937 cells via STAT6; TNF-α and IL-1β synergize with IL-4 at a step downstream of STAT6 activation. IFN-γ pre-treatment suppresses IL-4-mediated STAT6 phosphorylation and reduces total STAT6 protein, thereby inhibiting CCL26 expression.\",\n      \"method\": \"RT-PCR, ELISA, Western blot (STAT6 phosphorylation), cytokine stimulation combinations\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple cytokine conditions with signaling readouts, single lab\",\n      \"pmids\": [\"20059579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-13-induced CCL26 transcription is regulated epigenetically: CBP (CREB-binding protein), a histone acetyltransferase, promotes basal and IL-13-induced CCL26 promoter activity. IL-13 promotes formation of a CBP–STAT6 complex and histone H3 acetylation at the CCL26 promoter. CBP gene silencing decreases IL-13-induced CCL26 transcription; conversely, histone deacetylase inhibition increases it. A CRE site in the CCL26 promoter is required for IL-13-induced activity.\",\n      \"method\": \"Promoter-reporter assays, ChIP (histone acetylation, CBP, STAT6 occupancy), siRNA knockdown, HDAC inhibitor treatment\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter-reporter, ChIP, siRNA knockdown with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"21325281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-4 regulates CCL26 in keratinocytes via JAK1/JAK2–STAT6; serial 5′ promoter deletion and mutagenesis identified the proximal STAT6 site as the key response element; IL-4 activates STAT6 (not STAT3) and induces its nuclear translocation; JAK inhibitors suppress CCL26 upregulation in a dose-dependent manner.\",\n      \"method\": \"RT-PCR, ELISA, promoter-reporter assay, 5′ deletion series, site-directed mutagenesis, dominant-negative STAT studies, JAK inhibitors, Western blot (STAT3/6 phosphorylation), nuclear translocation assay\",\n      \"journal\": \"Molecular Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis, dominant-negative studies, nuclear translocation, multiple signaling inhibitors in one rigorous study\",\n      \"pmids\": [\"22226123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Omeprazole (and lansoprazole) blocks IL-4-stimulated CCL26 promoter activation and secretion in EoE esophageal epithelial cells by preventing nuclear binding of STAT6, RNA polymerase II, and trimethylated H3K4 to the endogenous CCL26 promoter, without affecting STAT6 phosphorylation or nuclear translocation, and without affecting CCL26 mRNA stability.\",\n      \"method\": \"ELISA, RT-PCR, Western blot (STAT6 phosphorylation/translocation), promoter-reporter construct, ChIP (STAT6, RNA Pol II, H3K4me3)\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP assays plus promoter reporter plus protein-level readouts, mechanistic dissection with multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"23185525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DNA demethylation of a specific CpG site (CpG 2) in the CCL26 promoter, juxtaposed to a CRE site, is associated with elevated basal and IL-13-induced CCL26 expression in allergic tissue-derived epithelial cells; CpG 2 methylation inversely correlates with CCL26 expression. EMSA demonstrated that CREB-binding protein and ATF-2 binding to the CRE site is methylation-dependent. 5-Azacytidine treatment promotes CCL26 production.\",\n      \"method\": \"Bisulfite sequencing, promoter-reporter assay (methylation-free in vitro system), 5-azacytidine treatment, EMSA\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — EMSA, methylation-free promoter reconstitution, bisulfite sequencing, and pharmacological validation in one study\",\n      \"pmids\": [\"24323578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL26 binds to CX3CR1 on NK cells and promotes F-actin reorganization and NK cell chemotaxis via a tyrosine kinase-sensitive pathway (genistein-sensitive); a single antigen nasal provocation challenge increases CX3CR1 expression on NK cells in allergic rhinitis patients, augmenting NK cell chemotaxis toward CCL26.\",\n      \"method\": \"Microchemotaxis chambers, flow cytometry, confocal microscopy (F-actin), genistein (tyrosine kinase inhibitor) blockade\",\n      \"journal\": \"Clinical and Experimental Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional chemotaxis with mechanistic inhibitor and cytoskeletal readout, single lab\",\n      \"pmids\": [\"23414540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL26 expression in colonic myofibroblasts is induced by IL-4 and IL-13 via STAT6; IFN-γ acts as a negative regulator via STAT1 activation. SOCS1 is also implicated as a regulatory component of the pathway.\",\n      \"method\": \"RT-PCR, ELISA, Western blot (STAT6/STAT1 signaling), cytokine stimulation\",\n      \"journal\": \"Clinical and Experimental Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple signaling readouts and cytokine conditions, single lab\",\n      \"pmids\": [\"23607908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL26 stimulates migration, invasion, and MMP2 activity of extravillous trophoblast-derived HTR8/SVneo cells, and increases cell adhesion to collagen IV and fibronectin; no effect on TIMP2 activity.\",\n      \"method\": \"xCELLigence real-time cell migration, wound-healing assay, Matrigel invasion assay, zymography (MMP2), reverse zymography (TIMP2), adhesion assay\",\n      \"journal\": \"Human Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays with recombinant CCL26, single lab and single cell line model\",\n      \"pmids\": [\"23477905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL26 exhibits direct bactericidal activity against airway pathogens (S. pneumoniae, S. aureus, H. influenzae, P. aeruginosa) via membrane disruption; the cationic/amphipathic COOH-terminal region is responsible for bactericidal activity. Mast cell chymase and tryptase cleave CCL26 to generate distinct fragments: the COOH-terminal fragment retains antibacterial activity, the NH2-terminal fragment has potent LPS-neutralizing activity, and neither fragment activates CCR3.\",\n      \"method\": \"Viable count assay, electron microscopy, bacterial membrane permeabilization assay, protease cleavage (chymase, tryptase), LPS neutralization assay, CCR3 activation assay\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal mechanistic assays (bactericidal, membrane disruption, fragment characterization, receptor activation) in a single rigorous study\",\n      \"pmids\": [\"25377782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAK-STAT6 pathway inhibitors (AS1517499, leflunomide, ruxolitinib) block Th2 cytokine-stimulated CCL26 expression in esophageal fibroblasts and epithelial cells by inhibiting STAT6 phosphorylation and nuclear translocation. Omeprazole does not inhibit cytokine-stimulated CCL26 expression in esophageal fibroblasts (negative result for omeprazole in fibroblasts vs. positive in epithelial cells).\",\n      \"method\": \"ELISA, Western blot (STAT6 phosphorylation/translocation), JAK-STAT inhibitor treatment, nuclear translocation assay\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors, multiple cell types, signaling and secretion readouts, single lab\",\n      \"pmids\": [\"27310888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-13-induced CCL26 expression in airway epithelial cells is mediated through a nongastric H,K-ATPase (encoded by ATP12A): knockdown of ATP12A significantly attenuates IL-13-induced CCL26 expression. PPIs block IL-13-enhanced H+/K+ exchange (detected by intracellular pH imaging) and CCL26 expression, and also accelerate IL-13-induced CCL26 mRNA decay.\",\n      \"method\": \"ELISA, Western blot, RT-PCR, intracellular pH imaging, siRNA knockdown (ATP12A), H,K-ATPase inhibitor (SCH-28080), extracellular K+ manipulation\",\n      \"journal\": \"The Journal of Allergy and Clinical Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — siRNA knockdown with mechanistic rescue (pH imaging, K+ manipulation), multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"27717558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CISH (a SOCS family member) is a negative regulator of IL-13-induced CCL26 production in human lung fibroblasts; CISH is itself induced by IL-13 via STAT6 phosphorylation. Loss-of-function (siRNA) increases CCL26, and gain-of-function (overexpression) decreases IL-13-induced CCL26 expression.\",\n      \"method\": \"cDNA microarray, quantitative RT-PCR, ELISA, Western blot, siRNA knockdown, vector overexpression\",\n      \"journal\": \"Allergology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function in primary cells, multiple readouts, single lab\",\n      \"pmids\": [\"30197185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"15-Lipoxygenase 1 (15LO1) promotes CCL26 expression in nasal epithelial cells via ERK activation: 15LO1 knockdown (DsiRNA) and enzymatic inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression; ERK inhibition alone also decreased IL-13-induced CCL26.\",\n      \"method\": \"Quantitative RT-PCR, Western blot (15LO1, CCL26, phospho-ERK), ELISA, ALOX15 DsiRNA knockdown, specific 15LO1 inhibitor, ERK inhibitors, air-liquid interface culture\",\n      \"journal\": \"The Journal of Allergy and Clinical Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — siRNA knockdown + enzymatic inhibitor + pathway inhibitor with multiple orthogonal readouts in primary cells\",\n      \"pmids\": [\"31301373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-4-stimulated CCL26 secretion in EoE esophageal squamous cells requires a nongastric H,K-ATPase (ngH+,K+ATPase; ATP12A) and intracellular calcium: IL-4 increases calcium via endoplasmic reticulum release (blocked by 2-APB) and L-type calcium channel entry (blocked by verapamil and diltiazem); chelation of intracellular calcium (EGTA-AM) blocks CCL26 secretion. Omeprazole and SCH-28080 also block IL-4-induced CCL26 secretion. Combined omeprazole + verapamil suppressed CCL26 more than either alone.\",\n      \"method\": \"ELISA, qRT-PCR, Western blot, Fluo-4 fluorescence (intracellular calcium), pharmacological inhibitors (omeprazole, SCH-28080, EGTA-AM, 2-APB, verapamil, diltiazem), primary EoE cells, RNA-seq validation\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple pharmacological dissections of distinct calcium pathways plus ngH+,K+ATPase, validated in primary cells and RNA-seq datasets\",\n      \"pmids\": [\"33581123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Airway epithelial cell-derived CCL26 activates CX3CR1+ alveolar macrophages via CCL26–CX3CR1 receptor-ligand interaction, inducing these macrophages to secrete C1q which facilitates eosinophil clearance, thereby resolving allergic lung eosinophilia. Conditional knockout of CCL26 in airway epithelial cells or depletion of CX3CR1 macrophages both delayed resolution with prolonged tissue eosinophilia.\",\n      \"method\": \"Mass cytometry, single-cell RNA sequencing, conditional CCL26 knockout mice, CX3CR1 macrophage depletion, biophysical binding assays, allergen bronchoprovocation (human), immunological assays\",\n      \"journal\": \"American Journal of Respiratory and Critical Care Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional knockout, cell depletion, receptor-ligand binding, scRNA-seq, human and mouse validation across multiple orthogonal approaches\",\n      \"pmids\": [\"36790376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CCL26 promoter activation by IL-13 requires the CRE site; the STAT6 pathway drives CCL26 expression but a CBP–STAT6 complex formation and subsequent histone H3 acetylation at the CCL26 promoter locus are mechanistically required for full transcriptional output.\",\n      \"method\": \"ChIP (CBP, STAT6, acetylated H3), promoter-reporter, CBP siRNA, HDAC inhibitor\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP plus promoter-reporter plus siRNA knockdown with multiple readouts in one study (same paper as PMID 21325281, listed separately above for epigenetic mechanism)\",\n      \"pmids\": [\"21325281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STAT6 phosphorylation inhibitors directly bind STAT6 and prevent its active dimer formation, blocking CCL26 secretion by bronchial epithelial cells stimulated with IL-4.\",\n      \"method\": \"Small molecule STAT6 inhibitor (compound R-84), ELISA (CCL26 secretion), STAT6 phosphorylation assay\",\n      \"journal\": \"Bioorganic & Medicinal Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitor with direct binding claim and functional readout, single lab single method\",\n      \"pmids\": [\"22217933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LTD4 potentiates IL-13-induced CCL26 release by airway epithelial cells via CysLT1 receptor upregulation; IL-13 first upregulates CysLT1 expression, increasing cellular responsiveness to LTD4 which then amplifies CCL26 secretion. LTD4 alone weakly induced CCL26; it had no effect on IL-4-stimulated cells.\",\n      \"method\": \"ELISA, RT-PCR, flow cytometry (CysLT1 expression), time-course stimulation\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ELISA and receptor expression with mechanistic ordering of pathway events, single lab\",\n      \"pmids\": [\"22952702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRL-3 (phosphatase of regenerating liver-3) upregulates CCL26 expression in colorectal cancer cells; CCL26 then binds CCR3 on tumor-associated macrophages (TAMs), mobilizing intracellular Ca2+ in TAMs and increasing IL-6 and IL-8 expression, which enhances colorectal cancer cell invasiveness.\",\n      \"method\": \"Gene ontology analysis, IHC (PRL-3, CCL26, CCR3), CCR3-CCL26 binding/co-culture assay, intracellular Ca2+ mobilization assay, Matrigel invasion assay, in vivo mouse injection model\",\n      \"journal\": \"Molecular Cancer Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-mediated calcium signaling, co-culture invasion assay, in vivo validation, single lab\",\n      \"pmids\": [\"29051319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCL26 promotes pancreatic cancer cell invasion via activation of the PI3K/AKT/mTOR pathway: recombinant CCL26 treatment of PDAC cell lines increased phosphorylation of PI3K, AKT, and mTOR, and enhanced invasiveness in Matrigel transwell assays.\",\n      \"method\": \"Transwell migration/invasion assay, Western blot (p-PI3K, p-AKT, p-mTOR), RT-qPCR, IHC, recombinant CCL26 treatment\",\n      \"journal\": \"Acta Biochimica et Biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — recombinant protein treatment with signaling readouts and functional invasion assay, single lab\",\n      \"pmids\": [\"33764366\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCL26 (eotaxin-3) is a secreted CC chemokine that functions as a selective CCR3 agonist recruiting eosinophils, basophils, and Th2 lymphocytes, and additionally acts as a functional agonist for CX3CR1 (recruiting NK cells and monocytes) while serving as a natural antagonist for CCR1, CCR2, and CCR5; its expression is induced by IL-4 and IL-13 predominantly via the JAK1/2–STAT6 pathway (with epigenetic amplification through CBP-mediated H3 acetylation and promoter demethylation) in epithelial cells, fibroblasts, keratinocytes, and monocytes, and is mechanistically controlled by a nongastric H+,K+-ATPase (ATP12A) and intracellular calcium signaling; on the cell surface it mediates eosinophil transepithelial migration in a membrane-bound form, and in the airway it drives eosinophil resolution via CCL26–CX3CR1-mediated activation of CX3CR1+ macrophages to secrete C1q.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCL26 (eotaxin-3) is a secreted CC chemokine that orchestrates Th2-type leukocyte trafficking and resolution by engaging multiple chemokine receptors with opposing functional outcomes [#0, #15]. It is a high-affinity functional agonist of CCR3, mobilizing calcium, driving actin polymerization, and chemoattracting eosinophils and basophils [#0, #2], and it additionally acts as a functional agonist of the fractalkine receptor CX3CR1, recruiting CD16+ NK cells, effector CD8+ T cells, and CD14low CD16high monocytes [#15, #22]. In parallel, CCL26 binds CCR1, CCR2, and CCR5 without activating them and instead behaves as a natural antagonist that suppresses responses to their cognate agonists and can drive Gi-dependent chemorepulsion of monocytes [#5, #7]. Beyond receptor signaling, CCL26 has direct bactericidal activity against airway pathogens through its cationic, amphipathic C-terminus, and mast-cell chymase/tryptase cleavage separates an antibacterial C-terminal fragment from an LPS-neutralizing N-terminal fragment [#25]. CCL26 expression is induced by the Th2 cytokines IL-4 and IL-13 through the JAK1/JAK2\\u2013STAT6 axis acting on a proximal STAT6 promoter element, with full transcriptional output requiring CBP\\u2013STAT6 complex formation, histone H3 acetylation, and promoter CpG demethylation adjacent to a CRE site [#11, #19, #18, #21]. Its induction is further gated by a nongastric H+,K+-ATPase (ATP12A) and intracellular calcium signaling, which is why proton-pump inhibitors block CCL26 in epithelial cells [#27, #30, #20]. Functionally, surface-bound CCL26 on IL-4-stimulated airway epithelium mediates eosinophil transepithelial migration via CCR3 [#12], while epithelial CCL26 also drives resolution of allergic eosinophilia by activating CX3CR1+ macrophages to secrete C1q and clear eosinophils [#31]. CCL26 additionally promotes migration and invasion of non-immune cells including fibroblasts, trophoblasts, and tumor cells [#16, #24, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established CCL26 as a bona fide functional chemokine by showing it is an agonist of CCR3, defining its primary receptor and eosinophil/basophil-recruiting role.\",\n      \"evidence\": \"Calcium flux, radioligand competition binding, and chemotaxis with recombinant baculovirus-expressed protein on CCR3+ cells and primary leukocytes\",\n      \"pmids\": [\"10488147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for receptor selectivity addressed\", \"In vivo relevance not yet tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the 3D fold and dynamics of CCL26, linking flexible N-terminal/N-loop regions to receptor binding and activation.\",\n      \"evidence\": \"NMR structure determination with 15N relaxation backbone dynamics\",\n      \"pmids\": [\"11425309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with any receptor\", \"Functional consequences of dynamic regions inferred, not mutated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed CCL26 is constitutively and IL-4-inducibly expressed by dermal fibroblasts and is equipotent with other eotaxins for chemotaxis but weaker for ROS release, hinting at signaling biases.\",\n      \"evidence\": \"RT-PCR, chemotaxis, actin polymerization, ROS, and calcium assays in primary fibroblasts\",\n      \"pmids\": [\"11286614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of reduced ROS efficacy unexplained\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed CCL26 as a multi-receptor regulator that antagonizes CCR2 and drives monocyte chemorepulsion, distinguishing it functionally from canonical agonist chemokines.\",\n      \"evidence\": \"Calcium, ERK, enzyme-release, and chemorepulsion assays with pertussis toxin blockade in transfected cells and monocytes\",\n      \"pmids\": [\"12689946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of antagonism vs agonism not resolved\", \"In vivo significance of chemorepulsion untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended CCL26's antagonist role to CCR1 and CCR5 and mapped distinct structural epitopes for its multiple receptor interactions.\",\n      \"evidence\": \"Radioligand binding, chemotaxis, calcium, actin assays in transfected cells plus 3D model epitope analysis\",\n      \"pmids\": [\"15039444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epitopes predicted from model, not co-crystallized\", \"No mutational confirmation of epitope assignments\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the JAK\\u2013STAT6 and MEK/ERK pathways and a proximal STAT6 promoter element as the core IL-4/IL-13 induction machinery for CCL26, distinguishing its regulation from eotaxin-1.\",\n      \"evidence\": \"Promoter deletion/mutagenesis, dominant-negative STAT6, JAK/MEK/p38/NF-\\u03baB inhibitors, signaling readouts across fibroblasts, epithelium, and keratinocytes\",\n      \"pmids\": [\"16755001\", \"15521376\", \"16045735\", \"15231490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific NF-\\u03baB effects unexplained\", \"Quantitative contribution of ERK vs STAT6 unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that surface-bound CCL26 on IL-4-stimulated epithelium is the operative form driving eosinophil transepithelial migration via CCR3, and that CCL26 autoregulates via CCR3.\",\n      \"evidence\": \"Transepithelial chemotaxis with antibody blockade, confocal surface localization, CCR3 antagonist and flow cytometry autoregulation studies\",\n      \"pmids\": [\"16983721\", \"15863444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of GAG vs protein anchoring not quantified\", \"In vivo membrane-bound role untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified CCL26 as a functional CX3CR1 agonist, broadening its target leukocyte repertoire to NK cells, effector T cells, and patrolling monocytes.\",\n      \"evidence\": \"Calcium flux, competition binding, in vitro and in vivo chemotaxis, HUVEC adhesion assays with human (not mouse) CX3CR1\",\n      \"pmids\": [\"20974991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species selectivity (human vs mouse CX3CR1) mechanistically unexplained\", \"Structural basis of CX3CR1 engagement unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined epigenetic control of CCL26 transcription, showing CBP\\u2013STAT6 complex formation, histone H3 acetylation, and a required CRE site for full IL-13-induced output.\",\n      \"evidence\": \"ChIP, promoter-reporter, CBP siRNA, and HDAC inhibitor assays\",\n      \"pmids\": [\"21325281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-specific CBP recruitment kinetics not detailed\", \"Interplay with other coactivators unmapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected CCL26 expression to promoter DNA methylation, showing CpG demethylation near the CRE site permits CBP/ATF-2 binding and elevated expression in allergic tissue.\",\n      \"evidence\": \"Bisulfite sequencing, methylation-free promoter reporters, 5-azacytidine treatment, and EMSA\",\n      \"pmids\": [\"24323578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes driving demethylation in allergic tissue unidentified\", \"Causality in patients correlational\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered a receptor-independent innate immune function of CCL26 as a direct bactericidal peptide and a protease-cleaved generator of distinct antibacterial and LPS-neutralizing fragments.\",\n      \"evidence\": \"Viable count, electron microscopy, membrane permeabilization, chymase/tryptase cleavage, LPS neutralization, and CCR3 activation assays\",\n      \"pmids\": [\"25377782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo antimicrobial relevance untested\", \"Physiological abundance of cleaved fragments unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the nongastric H+,K+-ATPase ATP12A and intracellular calcium as required upstream regulators of Th2-cytokine-induced CCL26, explaining proton-pump-inhibitor responsiveness.\",\n      \"evidence\": \"ATP12A siRNA knockdown, intracellular pH imaging, K+ manipulation, calcium imaging, and PPI/SCH-28080 treatment in epithelial and EoE cells\",\n      \"pmids\": [\"27717558\", \"33581123\", \"23185525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between H+/K+ exchange and STAT6-driven transcription incomplete\", \"Tissue specificity of PPI effect (epithelium vs fibroblasts) unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped negative feedback regulators of CCL26, with CISH and IFN-\\u03b3/STAT1 dampening STAT6-driven expression.\",\n      \"evidence\": \"Microarray, reciprocal siRNA/overexpression of CISH, and STAT1/STAT6 readouts in fibroblasts and myofibroblasts\",\n      \"pmids\": [\"30197185\", \"23607908\", \"20059579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative weight of feedback regulators in vivo unknown\", \"Mechanism of CISH action on STAT6 not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added 15-lipoxygenase-1/ERK as an amplifying input to IL-13-induced CCL26 in nasal epithelium, integrating lipid metabolism into chemokine induction.\",\n      \"evidence\": \"ALOX15 DsiRNA, enzymatic and ERK inhibitors with phospho-ERK and CCL26 readouts in air-liquid interface cultures\",\n      \"pmids\": [\"31301373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"15LO1 metabolite linking to ERK not identified\", \"Restricted to nasal epithelium\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established an in vivo resolution function for epithelial CCL26, which activates CX3CR1+ macrophages to secrete C1q and clear eosinophils, resolving allergic lung inflammation.\",\n      \"evidence\": \"Conditional epithelial CCL26 knockout and CX3CR1-macrophage depletion in mice, scRNA-seq, mass cytometry, binding assays, and human bronchoprovocation\",\n      \"pmids\": [\"36790376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of C1q-mediated eosinophil clearance not fully dissected\", \"Whether membrane-bound vs soluble CCL26 mediates macrophage activation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended CCL26 function to non-immune migration and tumor biology, promoting fibroblast/trophoblast/tumor cell invasion via CCR3-TAM crosstalk and PI3K/AKT/mTOR signaling.\",\n      \"evidence\": \"Invasion/migration assays, MMP2 zymography, CCR3 co-culture calcium signaling, PI3K/AKT/mTOR Western blots, and in vivo tumor models\",\n      \"pmids\": [\"20143648\", \"23477905\", \"29051319\", \"33764366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating tumor-cell-intrinsic PI3K/AKT signaling not defined\", \"In vivo causality for invasion limited to single models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CCL26's structural features dictate the switch between agonism (CCR3, CX3CR1) and antagonism (CCR1/2/5), and how membrane-bound versus soluble forms partition between recruitment and resolution functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor co-structures\", \"No structure-guided mutants tested across the full receptor panel\", \"Membrane vs soluble functional partitioning undefined in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0090729\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 31, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 18, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCR3\", \"CX3CR1\", \"CCR2\", \"CCR1\", \"CCR5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}