Affinage

IL4

Interleukin-4 · UniProt P05112

Round 2 corrected
Length
153 aa
Mass
17.5 kDa
Annotated
2026-04-28
130 papers in source corpus 46 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-4 is a pleiotropic type I cytokine that orchestrates type 2 immunity, tissue repair, and metabolic homeostasis by signaling through type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes to activate JAK–STAT6-dependent transcription, with additional context-specific engagement of IRS1–PI3K, AKT/MAPK, and transcription-independent pathways (PMID:8266078, PMID:18243101, PMID:25607842, PMID:29491183). In lymphocytes, IL-4 is non-redundantly required for Th2 differentiation, IgE class-switch recombination, and the broader Th2 cytokine program (IL-5, IL-9, IL-10), as demonstrated by IL-4-knockout and STAT6-knockout mice (PMID:8384701, PMID:8624821, PMID:2459206). IL-4 drives alternative (M2) macrophage polarization through STAT6-dependent SHIP degradation and KLF4 SUMOylation, promotes eosinophil-mediated beige fat biogenesis via macrophage catecholamine production, directly stimulates hepatocyte and resident macrophage proliferation during tissue repair, and programmes immunosuppressive myeloid progenitors in the tumor microenvironment (PMID:21469115, PMID:24906148, PMID:23716700, PMID:24101381, PMID:38057662). Negative regulation is enforced by Shp1-mediated dephosphorylation of STAT6, STUB1 (CHIP)-mediated ubiquitination and proteasomal degradation of IL-4Rα, and transcription-independent suppression of NLRP3 inflammasome assembly (PMID:23797092, PMID:24251647, PMID:25601272).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1986 High

    Cloning of human IL-4 established its identity as a dual T-cell and B-cell growth factor, resolving the molecular basis of 'B-cell stimulatory factor 1' activity.

    Evidence cDNA cloning from ConA-activated T-cell library, COS-7 expression, proliferation assays on T-cell clones and anti-IgM-activated B cells

    PMID:3016727

    Open questions at the time
    • Receptor identity unknown
    • Signaling pathway undetermined
    • In vivo requirement not yet tested
  2. 1988 High

    In vivo antibody neutralization and in vitro differentiation assays demonstrated that IL-4 is non-redundantly required for IgE production and directly promotes B-cell differentiation, establishing its central role in humoral type 2 immunity.

    Evidence Anti-IL-4 mAb in nematode-infected and anti-IgD-injected mice (99% IgE inhibition); purified B-cell differentiation assays

    PMID:2459206 PMID:3260922

    Open questions at the time
    • Molecular mechanism of isotype switching not resolved
    • Intracellular signaling pathway unknown
  3. 1988 Medium

    IL-4 was shown to modulate monocyte/macrophage phenotype—upregulating MHC class II while suppressing pro-inflammatory mediators—and to selectively increase endothelial adhesiveness for T cells, extending its functional scope beyond lymphocytes.

    Evidence Primary monocyte culture with flow cytometry and functional assays; endothelial adhesion assays with blocking antibodies

    PMID:1969883 PMID:3279117

    Open questions at the time
    • Monocyte signaling pathway uncharacterized
    • Identity of the T-cell-selective endothelial adhesion receptor unknown
  4. 1993 High

    IL-4 gene knockout mice and identification of STAT6 (IL-4 NAF) as a rapidly tyrosine-phosphorylated transcription factor resolved the non-redundant in vivo requirement for IL-4 in Th2 commitment and linked receptor engagement to a defined transcriptional mechanism.

    Evidence IL-4−/− mice with abolished Th2 cytokine program; EMSA/anti-phosphotyrosine supershift identifying STAT6 DNA-binding complex; γc cross-linking and IRS-1 phosphorylation

    PMID:7694370 PMID:8266078 PMID:8384701

    Open questions at the time
    • STAT6 gene not yet cloned
    • Relative contributions of STAT6 vs IRS pathways to different IL-4 responses unclear
  5. 1994 High

    Purification, cloning, and peptide-inhibition studies of STAT6 defined the direct receptor–transcription factor coupling mechanism, showing that phosphotyrosine motifs on IL-4Rα recruit and activate STAT6.

    Evidence Protein purification to homogeneity, cDNA cloning, phosphotyrosine peptide competition

    PMID:8085155

    Open questions at the time
    • Crystal structure of receptor–STAT6 interaction unavailable
    • Role of STAT6 dimerization in target gene selectivity unknown
  6. 1996 High

    STAT6 knockout mice demonstrated that virtually all canonical IL-4 biological responses—B-cell proliferation, MHC II upregulation, IgE production, Th2 differentiation—require STAT6, even though IL-4 activates other pathways.

    Evidence STAT6−/− mice with complete loss of IL-4-driven B-cell and T-cell responses; independently confirmed by two labs

    PMID:8602263 PMID:8624821

    Open questions at the time
    • STAT6-independent IL-4 functions not yet catalogued
    • Tissue-specific IL-4 responses (e.g., neuronal, metabolic) not examined
  7. 2000 High

    Identification of cis-regulatory elements controlling IL-4 gene expression—the CNS-1 locus control region and an intronic enhancer maintained by GATA/STAT5—revealed how coordinated Th2 cytokine gene expression is epigenetically regulated.

    Evidence YAC transgenic mice for CNS-1; DNase footprinting and methylation analysis for intronic enhancer with GATA/PU.1/STAT5 binding

    PMID:10753117 PMID:10975840

    Open questions at the time
    • Three-dimensional chromatin architecture of IL-4/IL-13/IL-5 locus not resolved
    • Cell-type-specific enhancer usage (mast cell vs Th2 vs Tfh) incompletely defined
  8. 2004 High

    Stochastic chromatin remodeling at a specific site (VA) in the IL-4 locus, requiring calcineurin/NFAT and an additional protein synthesis-dependent factor, explained the probabilistic nature of IL-4 expression at the single-cell level.

    Evidence Restriction enzyme accessibility assay with cyclosporin A and cycloheximide; single-cell cytokine capture

    PMID:14975241

    Open questions at the time
    • Identity of the cycloheximide-sensitive factor unknown
    • Relationship between VA accessibility and in vivo Th2 commitment kinetics unclear
  9. 2008 High

    Crystal structures of all three IL-4 receptor ternary complexes (type I and type II with IL-4; type II with IL-13) provided the structural basis for shared and divergent signaling through γc vs IL-13Rα1, explaining differential potency and cell-type specificity.

    Evidence X-ray crystallography of IL-4Rα/γc/IL-4, IL-4Rα/IL-13Rα1/IL-4, and IL-4Rα/IL-13Rα1/IL-13 complexes with cell-based signaling assays

    PMID:18243101

    Open questions at the time
    • No structure of full-length receptor with intracellular domains and associated JAKs
    • Mechanism of differential JAK activation (JAK3 vs TYK2) at the structural level unresolved
  10. 2013 High

    Conditional knockout studies revealed that IL-4 promotes tissue repair by directly acting on non-immune cells—hepatocytes for liver regeneration and resident macrophages for self-renewal—expanding its functional scope beyond classical immune regulation.

    Evidence Hepatocyte- and macrophage-specific IL-4Rα conditional knockouts in hepatectomy, toxin injury, and nematode infection models; BrdU/Ki67 proliferation assays

    PMID:23716700 PMID:24101381

    Open questions at the time
    • Intracellular pathway mediating hepatocyte proliferation not fully characterized
    • Whether IL-4-driven macrophage self-renewal contributes to tissue fibrosis in chronic settings unclear
  11. 2014 High

    Mechanistic studies of negative regulation identified STUB1-mediated ubiquitination/degradation of IL-4Rα and Shp1-mediated STAT6 dephosphorylation as feedback mechanisms, while a transcription-independent pathway was shown to suppress NLRP3 inflammasome assembly by blocking ASC oligomerization and NLRP3 mitochondrial redistribution.

    Evidence STUB1 KO mice with elevated IL-4Rα and spontaneous airway inflammation; T cell-specific Shp1 deletion with sustained STAT6; NLRP3 reconstitution with ASC oligomerization assay in STAT6 KO cells

    PMID:23797092 PMID:24251647 PMID:25601272

    Open questions at the time
    • STAT6-independent mechanism of NLRP3 suppression not molecularly identified
    • Relative contributions of STUB1 vs lysosomal IL-4Rα degradation in different cell types unknown
  12. 2015 High

    IL-4 was established as a neuroprotective and neuroregenerative cytokine: neuronal IL-4Rα signaling via AKT/MAPK and IRS1-PI3K-PKC pathways promotes axonal repair and functional recovery after CNS injury, independent of anti-inflammatory effects.

    Evidence Neuronal IL-4R conditional deletion in CNS injury and EAE models; intrathecal/nasal IL-4; pathway-level analysis of IRS1-PI3K-PKC and AKT/MAPK

    PMID:25607842 PMID:29491183

    Open questions at the time
    • Specific neuronal target genes downstream of IL-4-induced PKC activation uncharacterized
    • Whether neuronal IL-4R signaling is relevant in human neurological disease not established
  13. 2014 High

    Eosinophil-derived IL-4 was shown to drive beige fat biogenesis through alternatively activated macrophage catecholamine production and cardiac fibrotic remodeling in autoimmune myocarditis, revealing organ-specific pathological and metabolic circuits of IL-4.

    Evidence Cold exposure in IL-4/13-deficient and eosinophil-deficient mice; eosinophil-specific IL-4 conditional deletion in myocarditis model; macrophage tyrosine hydroxylase/catecholamine measurements

    PMID:24906148 PMID:28302646

    Open questions at the time
    • Whether beige fat IL-4 axis operates in adult humans is debated
    • Direct catecholamine production by macrophages has been challenged by subsequent studies
  14. 2023 High

    IL-4 was found to programme immunosuppressive myeloid cells at the bone marrow progenitor stage, with basophil/eosinophil-derived IL-4 acting on granulocyte-monocyte progenitors via IL-4Rα to establish tumour-promoting myeloid transcriptional states.

    Evidence Progenitor-specific vs mature myeloid IL-4Rα conditional knockouts; scRNA-seq; basophil depletion; dupilumab clinical observation

    PMID:38057662

    Open questions at the time
    • Whether dupilumab-mediated tumour regression is reproducible across cancer types not established
    • Epigenetic mechanism of progenitor imprinting by IL-4 uncharacterized
  15. 2024 High

    Spatial functional genomics demonstrated that tumour-derived IL-4 creates localized immunosuppressive niches by paracrine macrophage polarization, with loss of IL-4 in individual tumour clones producing immune-excluded microenvironments not compensated by neighbouring clones.

    Evidence Perturb-map spatial screen in ovarian cancer, IL-4 KO clones, anti-PD-1 therapy, TME macrophage phenotyping

    PMID:39481380

    Open questions at the time
    • Diffusion radius of IL-4 signaling in solid tumours not quantified
    • Whether IL-4 niche architecture predicts immunotherapy response in patients unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the molecular identity of the STAT6-independent mechanism by which IL-4 suppresses NLRP3 inflammasome assembly, the structural basis of full-length receptor–JAK complex activation, and whether IL-4 progenitor programming in the bone marrow can be therapeutically targeted without compromising protective type 2 immunity.
  • No structural model of full-length IL-4Rα/JAK/STAT6 signaling complex
  • STAT6-independent NLRP3 suppression mechanism unidentified
  • Therapeutic window for blocking IL-4 in cancer vs preserving helminth immunity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 7
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 2
Partners
IL13RA1IL2RGIL4RIRS1PTPN6STAT6STUB1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 Human IL-4 (then called B-cell stimulatory factor 1) was cloned from a concanavalin A-activated T-cell cDNA library. The encoded protein of 153 amino acids stimulates proliferation of human helper T-cell clones and anti-IgM-activated B cells, establishing its dual T-cell and B-cell stimulatory activities. cDNA cloning from human T-cell library, expression in COS-7 cells, proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 3016727
1988 IL-4 is required in vivo to generate and sustain IgE responses. Anti-IL-4 monoclonal antibody inhibited primary polyclonal IgE responses by 99% in nematode-infected or anti-IgD-injected mice and accelerated the decline of established IgE responses, demonstrating a non-redundant role for IL-4 in IgE production. In vivo antibody neutralization, serum IgE ELISA, mouse infection models Journal of immunology (Baltimore, Md. : 1950) High 2459206
1988 IL-4 directly induces differentiation of human precursor and pre-B cells into cytoplasmic µ- and surface IgM-positive cells without requiring cell proliferation, demonstrating a direct differentiation-promoting activity on early B-cell precursors. In vitro bone marrow culture, flow cytometry for cytoplasmic µ and surface IgM Journal of immunology (Baltimore, Md. : 1950) Medium 3260922
1988 IL-4 modulates human peripheral blood monocyte phenotype and function: it induces upregulation of MHC class II antigens, C3bi receptor, and p150.95, while inhibiting secretion of IL-1, cytostatic, and chemotactic compounds, suggesting IL-4 drives monocyte-to-macrophage differentiation and suppresses pro-inflammatory outputs. Primary monocyte culture, flow cytometry, functional cytostasis and chemotaxis assays Journal of immunology (Baltimore, Md. : 1950) Medium 3279117
1990 IL-4 acts directly on human vascular endothelial cells to increase their adhesiveness for T cells but not neutrophils, an effect blocked by anti-IL-4 but not anti-TNF antibodies, and mediated by generation of an alternative binding receptor distinct from ICAM-1/LFA-1. Endothelial cell adhesion assays, antibody blocking, T cell/neutrophil differential adhesion measurements Journal of immunology (Baltimore, Md. : 1950) Medium 1969883
1991 IL-4 plus hydrocortisone induces IgE isotype switching in normal purified peripheral blood B cells independent of T cells or monocytes; endogenous IL-6 was identified as a critical co-factor, as anti-IL-6 antibody strongly inhibited IgE production. Purified B cell culture, ELISA for IgE, antibody blocking, cell sorting Journal of immunology (Baltimore, Md. : 1950) Medium 1715363
1992 IL-4 enhances programmed cell death (apoptosis) in IL-1- or LPS-stimulated human monocytes but not in unstimulated cells, producing classic oligonucleosome-sized DNA laddering; this effect was antagonized by IFN-γ and was unique among tested cytokines. Monocyte viability assays, DNA ladder gel electrophoresis, cytokine competition experiments Journal of immunology (Baltimore, Md. : 1950) Medium 1541822
1993 Genetic disruption of the murine IL-4 gene (IL-4−/− mice) abolished Th2 cytokine responses (IL-5, IL-9, IL-10) and reduced helminth-induced eosinophilia, establishing IL-4 as required for generation of the Th2-derived cytokine program in vivo. Gene targeting/knockout mice, T-cell stimulation assays, cytokine ELISA, eosinophil counts after nematode infection Nature High 8384701
1993 IL-4 rapidly activates a tyrosine-phosphorylated DNA-binding factor (IL-4 NAF, later named STAT6) within minutes, which binds specific DNA sequences in IL-4-responsive gene promoters; activation required tyrosine phosphorylation as demonstrated by anti-phosphotyrosine antibody recognition of the NAF-DNA complex. EMSA, anti-phosphotyrosine antibody supershift, kinetics of nuclear factor activation Science (New York, N.Y.) High 7694370
1993 The IL-2 receptor γ chain (γc) is a functional component of the IL-4 receptor: chemical cross-linking and γc augmentation of IL-4 binding affinity were demonstrated, and γc was required for IL-4-mediated phosphorylation of insulin receptor substrate-1 (IRS-1/4PS). Chemical cross-linking, binding affinity measurements, IRS-1 phosphorylation assays Science (New York, N.Y.) High 8266078
1994 IL-4 Stat (STAT6) was purified to homogeneity, cloned, and characterized as a member of the STAT family. Phosphotyrosine-containing peptides from the intracellular domain of the IL-4 receptor inhibited IL-4 Stat activation, providing evidence for direct receptor–transcription factor coupling; the same domain mediates both receptor coupling and dimerization. Protein purification, peptide inhibition, cDNA cloning, sequence analysis Science (New York, N.Y.) High 8085155
1995 STAT6 (IL-4 Stat) is rapidly tyrosine-phosphorylated in response to IL-4 and IL-3, but not IL-2, IL-12, or erythropoietin; inducible tyrosine phosphorylation of STAT6 requires the membrane-distal region of the IL-4 receptor α chain, which is not required for mitogenesis—thus STAT6 activation is dissociated from proliferative signaling. STAT6-specific antiserum immunoprecipitation, cytokine stimulation panel, IL-4Rα truncation mutants Molecular and cellular biology High 7760829
1996 STAT6-deficient mice generated by gene targeting lack IL-4-induced upregulation of MHC class II and IL-4 receptor on B cells, fail to proliferate in response to IL-4, do not produce IgE after immunization, and fail to differentiate into Th2 cells in response to IL-4 or IL-13—establishing STAT6 as essential for mediating IL-4 biological responses despite the existence of other IL-4-activated pathways. Gene targeting, B-cell proliferation assays, FACS for surface markers, IgE ELISA, Th2 differentiation assays Immunity High 8602263 8624821
1997 p110δ, a novel class I PI3K exclusively expressed in leukocytes, associates with p85 adaptor proteins and is similarly recruited to activated signaling complexes after treatment with IL-4 (and IL-3/SCF), placing PI3K signaling in the IL-4 receptor pathway. cDNA cloning, immunoprecipitation, kinase assays, cytokine stimulation in leukocyte cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 9113989
1998 IL-4 induces eotaxin production in dermal fibroblasts: a single 13-kDa eosinophil-selective chemotaxin (eotaxin) was purified and identified biochemically; IL-4 dose- and time-dependently induced eotaxin mRNA, and synergy with TNF-α produced a 10–20-fold increase in eotaxin release—providing a mechanistic basis for eosinophil recruitment in IL-4-mediated skin reactions. HPLC purification, SDS-PAGE, peptide mapping/sequencing, RT-PCR, chemotaxis assays Journal of immunology (Baltimore, Md. : 1950) High 9551956
1998 GATA-3 acts through GATA binding sites in genomic regions surrounding the IL-4 locus as a permissive but not sufficient enhancer of IL-4 transcription in Th2 cells; retroviral GATA-3 transduction induced IL-5 to full Th2 levels but only partially restored IL-4 production, indicating additional factors are required. Reporter gene assays, EMSA for GATA binding, retroviral transduction of T cells, transgenic mouse analysis Journal of immunology (Baltimore, Md. : 1950) Medium 9780146
1998 IL-4 requires STAT6 and IL-4Rα to exacerbate anaphylaxis; pretreatment with IL-4 dramatically increased severity of anaphylaxis induced by FcεRI or FcγRIII crosslinking. The mechanism involves IL-4 acting synergistically with vasoactive mediators to increase vascular permeability, independently of T cells, B cells, and common γ-chain, but requiring IL-4Rα and Stat6. In vivo mouse anaphylaxis models, genetic knockout mice (STAT6−/−, IL-4Rα−/−), vascular permeability assays, cytokine pretreatment experiments Journal of immunology (Baltimore, Md. : 1950) High 12646651
2000 A conserved noncoding element (CNS-1) located ~650 bp upstream of the IL-4 promoter was identified as a coordinate cis-regulatory element governing co-expression of IL-4, IL-13, and IL-5 across 120 kb; YAC transgenic mice showed this element is required for full Th2-specific expression of all three cytokines. Cross-species sequence conservation analysis, YAC transgenic mice, reporter gene assays Science (New York, N.Y.) High 10753117
2000 An intronic transcriptional enhancer element in intron 2 of the murine IL-4 gene maintains locus accessibility in mast cells through GATA-1/2, PU.1, and STAT5a/STAT5b binding; deletion of this element or mutation of the GATA site in a stably integrated IL-4 genomic construct prevents maintenance of a demethylated IL-4 locus, indicating a role analogous to Ig/TCR intron regulatory elements. DNase I footprinting, mutational analysis, stable genomic integration, methylation analysis Journal of immunology (Baltimore, Md. : 1950) High 10975840
2000 IL-4 increases FasL expression on CD4+ and CD8+ T cells in vivo, shifting CTL killing from a dominant perforin-mediated pathway to a dominant Ca2+-independent Fas/FasL pathway, as demonstrated by recombinant vaccinia virus coexpressing antigen and IL-4. Recombinant vaccinia virus expression, EGTA/Mg2+ chelation to dissect killing pathways, flow cytometry for FasL, cytotoxicity assays with Fas+/− targets Journal of immunology (Baltimore, Md. : 1950) Medium 10725701
2000 IL-4 expression in Clara cells of transgenic mice drives IL-4-dependent increases in surfactant phosphatidylcholine synthesis and clearance, and selectively induces SP-D mRNA ~2.8-fold and protein ~90-fold, establishing a previously unrecognized IL-4 role in pulmonary surfactant homeostasis. Transgenic mouse lung analysis, radiolabeled lipid incorporation, Northern/Western blot for surfactant proteins American journal of physiology. Lung cellular and molecular physiology Medium 10645893
2004 IL-4 probabilistically regulates IL-4 production at the single-cell level through stochastic opening of a chromatin site (VA, 5 kb 3′ of exon 4); this opening requires calcineurin/NFAT (blocked by cyclosporin A) and an additional cycloheximide-sensitive factor; producers and nonproducers have similar GATA-3/c-maf levels and similar accessibility at other IL-4 locus sites. Restriction enzyme accessibility (REA) assay, cyclosporin A treatment, cycloheximide treatment, single-cell cytokine capture Immunity High 14975241
2006 IL-4 induces TARC/CCL17 expression in human T cells via two STAT6 binding sites in the CCL17 promoter; EMSA and chromatin immunoprecipitation confirmed direct STAT6 binding; mutation of both sites completely abolished IL-4 inducibility in reporter assays, establishing a STAT6-dependent direct transcriptional mechanism. ChIP, EMSA, promoter reporter assays, STAT6-deficient cell line reconstitution European journal of immunology High 16810739
2006 IL-4, acting through the type 1 IL-4R (IL-4Rα/γc) and requiring STAT6, induces IFN-γ production by NK and NKT cells in vivo within 2–4 hours; IL-13, which signals only through the type 2 IL-4R (IL-4Rα/IL-13Rα1), fails to stimulate IFN-γ and even suppresses basal IFN-γ production—establishing distinct functional outcomes of type 1 vs type 2 IL-4R signaling. In vivo cytokine capture assay, anti-IL-2Rβ NK depletion, Rag2/γc double KO mice, STAT4 KO mice, STAT6 KO mice, cytokine neutralization Journal of immunology (Baltimore, Md. : 1950) High 16621996
2007 TSLP drives Th2 differentiation independently of exogenous IL-4 by directly inducing IL-4 gene transcription in CD4+ T cells; this process requires STAT6 and is independent of IL-2, establishing a TSLP→IL-4→STAT6 positive-feedback pathway. In vitro Th2 differentiation with anti-IL-4 blocking, STAT6 KO T cells, IL-4 mRNA kinetics by RT-PCR Journal of immunology (Baltimore, Md. : 1950) Medium 17237387
2008 Crystal structures of the complete type I (IL-4Rα/γc/IL-4) and type II (IL-4Rα/IL-13Rα1/IL-4 and IL-4Rα/IL-13Rα1/IL-13) ternary signaling complexes revealed: (1) structural basis for γc recognition of six different γc-cytokines; (2) IL-13Rα1 uses an unusual top-mounted Ig-like domain for cytokine engagement; (3) reversed assembly sequences for type I vs type II complexes mediated by different recognition chemistries; (4) the type II heterodimer signals with different potencies for IL-4 vs IL-13, with extracellular interactions modulating intracellular membrane-proximal signaling. X-ray crystallography of ternary complexes, cell-based signaling potency assays Cell High 18243101
2011 Alternative (M2) macrophage activation by IL-4 requires STAT6-dependent degradation of SHIP; IL-4-treated macrophages show decreased SHIP protein levels dependent on PI3K activity (specifically class IA PI3Kp110δ isoform); reducing SHIP enhanced, while SHIP overexpression reduced, IL-4-induced arginase I activity—identifying SHIP as a PI3K-regulated negative regulator of IL-4-driven M2 polarization. SHIP KO macrophages, PI3K inhibitors, SHIP siRNA knockdown, SHIP overexpression, arginase activity assays, STAT6 KO cells European journal of immunology High 21469115
2011 Direct IL-4Rα stimulation of smooth muscle is sufficient (but not necessary) to induce airway hyperresponsiveness (AHR); transgenic mice in which smooth muscle is the only cell expressing or lacking IL-4Rα demonstrated that IL-4, IL-13, or allergen acting on smooth muscle alone activates five genes promoting smooth muscle migration, proliferation, and contractility. Cell-type-specific IL-4Rα transgenic and conditional knockout mice, methacholine challenge (AHR measurement), gene expression profiling The Journal of experimental medicine High 21464224
2012 IL-4 inhibits melanogenesis in normal human melanocytes via the JAK2-STAT6 signaling pathway: IL-4 treatment increased STAT3 and STAT6 phosphorylation; the JAK2 inhibitor AG490 or STAT6 siRNA blocked IL-4-induced downregulation of MITF and dopachrome tautomerase expression. Primary human melanocyte culture, Western blot for STAT phosphorylation, RT-PCR, JAK2 inhibitor, STAT6 siRNA knockdown The Journal of investigative dermatology Medium 22992805
2013 IL-4 derived from eosinophils stimulates hepatocyte proliferation via IL-4Rα on hepatocytes to promote liver regeneration after partial hepatectomy and toxin-mediated injury; macrophage IL-4Rα signaling was found dispensable, establishing direct IL-4→hepatocyte IL-4Rα→proliferation as the operative pathway. Partial hepatectomy and toxin injury models, eosinophil-deficient mice, macrophage-specific and hepatocyte-specific IL-4Rα conditional knockouts, BrdU incorporation Proceedings of the National Academy of Sciences of the United States of America High 23716700
2013 IL-4 converts tissue-resident macrophages from a CSF-1-dependent to a CSF-1-independent proliferation program via macrophage-intrinsic IL-4Rα signaling; IL-4Rα expression confers a competitive advantage with higher and more sustained proliferation; unlike CSF-1, the IL-4 pathway expands resident macrophage density without triggering monocyte or neutrophil recruitment. Nematode infection models, macrophage-specific IL-4Rα conditional knockout mice, mixed bone marrow chimeras, BrdU/Ki67 proliferation assays, competitive reconstitution The Journal of experimental medicine High 24101381
2013 Shp1 (PTPN6) negatively regulates IL-4 signaling in T cells: T cell-specific Shp1 deletion leads to sustained STAT6 activation after IL-4 stimulation, skewing toward Th2 lineage and elevated serum IgE; IL-4 blockade or genetic IL-4 deletion in Shp1-deficient mice abolished the CD44hi memory T-cell phenotype, placing Shp1 as a negative regulator of IL-4/STAT6 signaling. T cell-specific Cre/lox Shp1 deletion, Shp1fl/fl IL-4−/− double KO, STAT6 phosphorylation kinetics, flow cytometry, serum IgE ELISA The Journal of experimental medicine High 23797092
2014 STUB1 (CHIP E3 ubiquitin ligase) interacts with IL-4Rα and targets it for ubiquitination-mediated proteasomal degradation, thereby terminating IL-4/IL-13 signaling; STUB1 knockout cells show increased IL-4Rα levels and sustained STAT6 activation; STUB1 overexpression reduced IL-4Rα levels; STUB1-deficient mice develop spontaneous airway inflammation and elevated IgE. Co-immunoprecipitation, ubiquitination assay, flow cytometry, STUB1 KO mice, STUB1 overexpression American journal of respiratory and critical care medicine High 24251647
2014 IL-4 suppresses NLRP3 inflammasome activation in macrophages via a transcription-independent mechanism: IL-4 inhibits NLRP3-dependent ASC oligomerization, NLRP3-ASC interaction, and speck formation, and blocks subcellular redistribution of NLRP3 into mitochondria and microtubule polymerization; this suppression is STAT6-independent and mitochondrial ROS-independent. NLRP3 inflammasome reconstitution in macrophages, ASC oligomerization assay, NLRP3-ASC co-IP, immunofluorescence for NLRP3 localization, STAT6 KO cells, microtubule inhibitors Immunology and cell biology High 25601272
2014 Eosinophil-derived IL-4 and alternatively activated macrophages constitute an efferent circuit for cold-induced beige fat biogenesis: genetic loss of eosinophils or IL-4/IL-13 signaling impairs cold-induced beige fat development; mechanistically, macrophages recruited to cold-stressed white adipose tissue undergo alternative activation to upregulate tyrosine hydroxylase and produce catecholamines required for tissue browning. Eosinophil-deficient mice, IL-4/13 signal-deficient mice, cold exposure, UCP1 expression, macrophage adoptive transfer, tyrosine hydroxylase expression/catecholamine measurements Cell High 24906148
2015 Batf, in cooperation with IRF4, STAT3, and STAT6, drives IL-4 production specifically in T follicular helper (Tfh) cells by directly binding and activating the CNS2 region of the IL-4 locus; Batf deficiency impairs IL-4-producing Tfh cells without affecting canonical Th2 cells; Batf-to-c-Maf signaling is also required for Tfh IL-4 expression. ChIP, Batf conditional knockout mice, Tfh adoptive transfer, cytokine ELISA, asthma model Nature communications High 26278622
2015 T cell-derived IL-4 protects and promotes recovery of injured neurons by activating neuronal IL-4 receptors, which potentiate neurotrophin signaling via the AKT and MAPK pathways; neuronal deletion of IL-4R abrogated IL-4-mediated functional recovery in CNS injury models. Two murine CNS injury models, neuronal IL-4R conditional deletion, wild-type vs IL-4 KO T-cell transfer, neuron culture + IL-4 treatment, AKT/MAPK pathway analysis The Journal of clinical investigation High 25607842
2017 Eosinophil-derived IL-4 drives progression of autoimmune myocarditis to inflammatory dilated cardiomyopathy (DCMi); IL-4−/− mice are protected from DCMi like eosinophil-deficient mice; eosinophil-specific IL-4 deletion recapitulated this protection, establishing eosinophil-derived IL-4 as the mechanistic driver of cardiac fibrotic remodeling. Experimental autoimmune myocarditis model, IL-4 KO, eosinophil-deficient ΔdblGATA1 mice, IL-5Tg hypereosinophilic mice, eosinophil-specific IL-4 conditional deletion, echocardiography The Journal of experimental medicine High 28302646
2017 SUMOylation of KLF4 is induced by IL-4 treatment in macrophages and is required for IL-4-driven M2 polarization; SUMOylation-defective KLF4 failed to promote M2 markers in RAW264.7 cells and BMDMs, identifying KLF4 SUMOylation as a post-translational mechanism downstream of IL-4 signaling. SUMOylation assays, KLF4 mutant overexpression, BMDMs and RAW264.7 macrophage polarization assays, flow cytometry Cell cycle (Georgetown, Tex.) Medium 28059602
2018 IL-4 exerts direct neuronal signaling via the IRS1-PI3K-PKC pathway to promote cytoskeletal remodeling and axonal repair; intrathecal IL-4 reversed disease progression in chronic EAE without affecting inflammation; neuronal deletion of IL-4R abolished the benefit, and nasal delivery was equally effective. Multiple EAE models, neuronal IL-4R conditional deletion, intrathecal/nasal IL-4 administration, IRS1-PI3K-PKC pathway analysis, cytoskeletal readouts Science translational medicine High 29491183
2018 IVIG induces IL-4 secretion in human basophils by interacting with basophil surface-bound IgE via F(ab')2 fragments through the spleen tyrosine kinase (Syk) pathway; this effect is independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins. Basophil isolation, Syk pathway inhibitors, blocking antibodies for multiple Fc/lectin receptors, IVIG fragment (F(ab')2 vs Fc) experiments, CD69/cytokine ELISA The Journal of allergy and clinical immunology Medium 30529242
2019 NKT2 cells in the thymic medulla require continuous TCR stimulation for constitutive IL-4 production; hematopoietic (not stromal) APCs provide this signal; macrophages are the predominant APCs stimulating NKT2 IL-4 production, as demonstrated by CD1d cell-specific deletion and diphtheria toxin-mediated depletion of specific APC populations. Intrathymic transfer into CD1d-deficient hosts, bone marrow chimeras, APC-specific Cre CD1d deletion, DTR-mediated depletion, histocytometry Proceedings of the National Academy of Sciences of the United States of America High 31611396
2021 Wnt signaling potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis during atherosclerosis resolution; IL-4-deficient mice show impaired resolution; Wnt pathway activation enhances expression of inflammation-resolving factors after low-concentration IL-4 treatment, mechanistically linking Wnt and IL-4/STAT6 pathways. Il4 KO mice atherosclerosis resolution model, Wnt pathway modulation, PGE2/STAT3 pathway inhibition, macrophage gene expression eLife Medium 33720008
2023 IL-4 derived from bone marrow basophils and eosinophils acts on granulocyte-monocyte progenitors via IL-4Rα to transcriptionally programme immunosuppressive tumour-promoting myeloid cells; only deletion of IL-4Rα in early myeloid progenitors (not mature myeloid cells) reduced tumour burden, establishing a bone marrow–level IL-4 signalling axis in cancer immunosuppression. Single-cell RNA sequencing, panel of conditional IL-4Rα knockout mice (progenitor-specific vs mature myeloid), basophil depletion, clinical trial with IL-4Rα blocking antibody dupilumab Nature High 38057662
2024 Ovarian cancer cells are a key source of IL-4 that drives formation of an immunosuppressive TME via macrophage control; IL-4 loss from cancer clones creates short-range immune-excluded niches not compensated by neighboring IL-4-expressing clones, revealing localized paracrine regulation of TME composition and immunotherapy resistance. Perturb-map spatial functional genomics screen, IL-4 knockout in tumor clones, anti-PD-1 treatment, TME macrophage characterization Cell High 39481380

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 Requirement for IL-13 independently of IL-4 in experimental asthma. Science (New York, N.Y.) 1477 9856950
1996 Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1273 8624821
1996 Essential role of Stat6 in IL-4 signalling. Nature 1237 8602263
2009 Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nature genetics 1160 19169254
1993 Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 1067 8384701
2007 Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell stem cell 865 18371377
1993 Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science (New York, N.Y.) 804 8266078
1994 An interleukin-4-induced transcription factor: IL-4 Stat. Science (New York, N.Y.) 776 8085155
2014 Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 717 24906148
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2000 Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science (New York, N.Y.) 626 10753117
1988 IL-4 is required to generate and sustain in vivo IgE responses. Journal of immunology (Baltimore, Md. : 1950) 624 2459206
1986 Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities. Proceedings of the National Academy of Sciences of the United States of America 618 3016727
2006 B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. The Journal of experimental medicine 570 16606666
2007 Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. The Journal of biological chemistry 462 17623648
2008 Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 447 18243101
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2012 IL-4 in the brain: a cytokine to remember. Journal of immunology (Baltimore, Md. : 1950) 436 23087426
2016 IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nature immunology 402 27111145
1997 P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proceedings of the National Academy of Sciences of the United States of America 383 9113989
2015 IL-4 and IL-13 signaling in allergic airway disease. Cytokine 377 26070934
2015 T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine 368 26044597
2004 Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. The Journal of experimental medicine 337 15314076
2013 IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. The Journal of experimental medicine 320 24101381
1988 Modulation of phenotypic and functional properties of human peripheral blood monocytes by IL-4. Journal of immunology (Baltimore, Md. : 1950) 300 3279117
1995 Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Molecular and cellular biology 287 7760829
1993 Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science (New York, N.Y.) 253 7694370
2018 Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 247 30022164
2015 The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 243 26073683
1998 IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy. Journal of immunology (Baltimore, Md. : 1950) 236 9551956
1993 Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proceedings of the National Academy of Sciences of the United States of America 236 8516290
2005 Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. Journal of immunology (Baltimore, Md. : 1950) 225 15661875
2013 Eosinophils secrete IL-4 to facilitate liver regeneration. Proceedings of the National Academy of Sciences of the United States of America 224 23716700
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
2008 IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. Journal of immunology (Baltimore, Md. : 1950) 222 18641314
2015 miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nature communications 221 26436920
1997 HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B. Nature medicine 220 9334723
1990 IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils. Journal of immunology (Baltimore, Md. : 1950) 214 1969883
2005 Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 212 16380445
2010 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis and rheumatism 211 20039421
2015 Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine 190 26088753
2007 Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. Journal of immunology (Baltimore, Md. : 1950) 189 17237387
2003 Dual roles of IL-4 in lung injury and fibrosis. Journal of immunology (Baltimore, Md. : 1950) 187 12574379
1999 IL-4 enhances proliferation and mediator release in mature human mast cells. Proceedings of the National Academy of Sciences of the United States of America 172 10393951
2010 IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. Journal of immunology (Baltimore, Md. : 1950) 154 20147633
2015 MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. The Journal of clinical investigation 151 25607842
1998 GATA-3-dependent enhancer activity in IL-4 gene regulation. Journal of immunology (Baltimore, Md. : 1950) 145 9780146
1991 Hydrocortisone and IL-4 induce IgE isotype switching in human B cells. Journal of immunology (Baltimore, Md. : 1950) 141 1715363
2023 An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 135 38057662
1992 IL-4 enhances programmed cell death (apoptosis) in stimulated human monocytes. Journal of immunology (Baltimore, Md. : 1950) 135 1541822
1998 Regulation of IL-4 expression by activation of individual alleles. Immunity 134 9729042
2009 Paradoxical roles of IL-4 in tumor immunity. Cellular & molecular immunology 128 20003817
2004 IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. Journal of immunology (Baltimore, Md. : 1950) 126 15100288
1999 The R576 IL-4 receptor alpha allele correlates with asthma severity. The Journal of allergy and clinical immunology 116 10550746
2021 Recent advances in understanding the role of IL-4 signaling. Faculty reviews 111 34557875
2003 IL-4 exacerbates anaphylaxis. Journal of immunology (Baltimore, Md. : 1950) 105 12646651
2015 Batf is important for IL-4 expression in T follicular helper cells. Nature communications 97 26278622
2012 Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Molecular neurodegeneration 97 22838967
2006 IL-4 induces IL-13-independent allergic airway inflammation. The Journal of allergy and clinical immunology 97 16890766
2004 IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils. Journal of immunology (Baltimore, Md. : 1950) 93 14764670
2000 IL-4 enhances keratinocyte expression of CXCR3 agonistic chemokines. Journal of immunology (Baltimore, Md. : 1950) 90 10903743
2017 Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy. The Journal of experimental medicine 85 28302646
2011 Alternative activation of macrophages by IL-4 requires SHIP degradation. European journal of immunology 83 21469115
2013 Shp1 regulates T cell homeostasis by limiting IL-4 signals. The Journal of experimental medicine 80 23797092
2024 Ovarian cancer-derived IL-4 promotes immunotherapy resistance. Cell 78 39481380
2018 NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma. The Biochemical journal 78 29626160
2012 IL-4 inhibits the melanogenesis of normal human melanocytes through the JAK2-STAT6 signaling pathway. The Journal of investigative dermatology 77 22992805
2009 The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity. Journal of immunology (Baltimore, Md. : 1950) 77 19587014
2006 IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. European journal of immunology 77 16810739
1988 IL-4 regulates differentiation and proliferation of human precursor B cells. Journal of immunology (Baltimore, Md. : 1950) 77 3260922
2011 Sensitivity and resistance to regulation by IL-4 during Th17 maturation. Journal of immunology (Baltimore, Md. : 1950) 72 21949021
1996 IL-4 upregulates tenascin synthesis in scleroderma and healthy skin fibroblasts. The Journal of investigative dermatology 72 8941674
2022 IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity. Molecular therapy : the journal of the American Society of Gene Therapy 70 35292359
2021 Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer. International journal of molecular sciences 67 33804263
2011 Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice. The Journal of experimental medicine 67 21464224
2001 IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer research 67 11306493
2016 IL-4 impairs wound healing potential in the skin by repressing fibronectin expression. The Journal of allergy and clinical immunology 66 27554818
1994 Decreased mucosal interleukin-4 (IL-4) production in gut inflammation. Journal of clinical pathology 66 7829675
1993 IL-4 release by human leukemic and activated normal basophils. Journal of immunology (Baltimore, Md. : 1950) 66 7687630
2004 Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus. Immunity 65 14975241
2001 IL-4 exacerbates disease in a Th1 cell transfer model of colitis. Journal of immunology (Baltimore, Md. : 1950) 63 11160346
2014 IL-4, JAK-STAT signaling, and pain. JAK-STAT 62 24470980
2002 Overexpression of IL-4 alters the homeostasis in the skin. The Journal of investigative dermatology 61 11982753
2018 Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. Science translational medicine 60 29491183
1993 Synovial fluid macrophages and blood monocytes differ in their response to IL-4. Journal of immunology (Baltimore, Md. : 1950) 60 7690805
2016 StarPEG-Heparin Hydrogels to Protect and Sustainably Deliver IL-4. Advanced healthcare materials 59 27860466
1996 Early IL-4 production does not predict susceptibility to Leishmania major. Experimental parasitology 59 8932767
2024 Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages. Science (New York, N.Y.) 55 38574142
2000 IL-4 increases surfactant and regulates metabolism in vivo. American journal of physiology. Lung cellular and molecular physiology 55 10645893
2000 An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. Journal of immunology (Baltimore, Md. : 1950) 54 10975840
2017 Functions of IL-4 and Control of Its Expression. Critical reviews in immunology 53 29773020
2015 The evolution of IL-4 and IL-13 and their receptor subunits. Cytokine 53 26005057
2014 Regulation of IL-4 receptor signaling by STUB1 in lung inflammation. American journal of respiratory and critical care medicine 53 24251647
2001 (S)-albuterol increases the production of histamine and IL-4 in mast cells. International archives of allergy and immunology 51 11340331
2023 Induction of unique macrophage subset by simultaneous stimulation with LPS and IL-4. Frontiers in immunology 49 37180123
2021 Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis. eLife 48 33720008
1995 IL-4 renders mast cells functionally responsive to endothelin-1. Journal of immunology (Baltimore, Md. : 1950) 48 7530742
2000 IL-4 diminishes perforin-mediated and increases Fas ligand-mediated cytotoxicity In vivo. Journal of immunology (Baltimore, Md. : 1950) 47 10725701
1999 Retrovirally induced switch from production of IL-12 to IL-4 in dendritic cells. European journal of immunology 46 10427994
1999 Stat6-dependent and -independent pathways for IL-4 production. Journal of immunology (Baltimore, Md. : 1950) 46 10586046
2018 Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE. The Journal of allergy and clinical immunology 45 30529242
2019 Synergistic regulation of osteoimmune microenvironment by IL-4 and RGD to accelerate osteogenesis. Materials science & engineering. C, Materials for biological applications 44 32228925
2016 IL-4 rescues surface IgM expression in chronic lymphocytic leukemia. Blood 44 27226435
2017 Synergistic mucus secretion by histamine and IL-4 through TMEM16A in airway epithelium. American journal of physiology. Lung cellular and molecular physiology 43 28546154
2015 Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury. PLoS pathogens 43 26720604
2009 Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 43 19155490
2019 Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. Proceedings of the National Academy of Sciences of the United States of America 42 31611396
2014 The role of IL-4 and IL-13 in cutaneous Leishmaniasis. Immunology letters 42 24412597
2007 IL-4 suppresses dendritic cell response to type I interferons. Journal of immunology (Baltimore, Md. : 1950) 41 17982033
2006 IL-4 induces in vivo production of IFN-gamma by NK and NKT cells. Journal of immunology (Baltimore, Md. : 1950) 41 16621996
2017 SUMOylation of KLF4 promotes IL-4 induced macrophage M2 polarization. Cell cycle (Georgetown, Tex.) 40 28059602
2005 Suppressive effect of IL-4 on IL-13-induced genes in mouse lung. Journal of immunology (Baltimore, Md. : 1950) 40 15814686
2003 IL-4 and many roads to lupuslike autoimmunity. Clinical immunology (Orlando, Fla.) 40 12921752
2007 CCL23 expression is induced by IL-4 in a STAT6-dependent fashion. Journal of immunology (Baltimore, Md. : 1950) 38 17371990
1999 IL-4 selectively inhibits IL-2-triggered Stat5 activation, but not proliferation, in human T cells. Journal of immunology (Baltimore, Md. : 1950) 38 9973378
2023 Requirements of IL-4 during the Generation of B Cell Memory. Journal of immunology (Baltimore, Md. : 1950) 37 37276051
2003 Effects of IL-4 on conjunctival fibroblasts: possible role in ocular cicatricial pemphigoid. Investigative ophthalmology & visual science 36 12882790
1996 Role of IL-4 in delayed type hypersensitivity. Clinical and experimental immunology 36 8565267
2021 Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4. Science advances 35 34134993
2004 IL-4 induces production of the lung collectin surfactant protein-D. The Journal of allergy and clinical immunology 35 15007344
2000 Activation of the IL-4 STAT pathway in rheumatoid synovium. Journal of immunology (Baltimore, Md. : 1950) 34 10725752
2015 Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4. Immunology and cell biology 33 25601272
2005 Interleukin-4 (IL-4) pathway. Science's STKE : signal transduction knowledge environment 32 16030287
2003 IL-4 biology: impact on normal and leukemic CLL B cells. Leukemia & lymphoma 32 12854886
2000 Relationships between natural T cells, atopy, IgE levels, and IL-4 production. Allergy 32 10753021
2021 IL-4 expressing cells are recruited to nerve after injury and promote regeneration. Experimental neurology 31 34717939
2002 IL-4 regulation of p38 MAPK signalling is dependent on cell type. Cytokine 30 12160517
2000 Increased sensitivity to IL-4 in patients with allergic bronchopulmonary aspergillosis. International archives of allergy and immunology 30 11146389