Interleukin-4 (IL-4) is a secreted four-helix bundle cytokine of the IL-4/IL-13 family, produced primarily by Th2 cells, basophils, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s). It functions as the master regulator of type 2 immunity by binding the IL-4 receptor alpha chain (IL4RA) and signaling through two receptor complexes: the type I complex (IL4RA/IL2RG) on hematopoietic cells, and the type II complex (IL4RA/IL13RA1) on non-hematopoietic and some hematopoietic cells. IL-4 signals canonically through JAK1/JAK3-STAT6, leading to GATA3 induction that drives Th2 differentiation, B cell class switch recombination to IgE and IgG4, MHC class II upregulation on B cells, and M2 macrophage polarization. IL-4 also activates IRS-2/PI3K pathways contributing to cell survival and proliferation. It is a central mediator of allergic inflammation, anti-helminth defense, and various immune regulatory processes. The protein has three disulfide bonds (Cys3-Cys127, Cys24-Cys65, Cys46-Cys99) and one N-glycosylation site (Asn62). An alternatively spliced isoform (IL-4delta2) lacking exon 2 acts as a natural antagonist.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0035771 interleukin-4-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IL-4 is the defining ligand of the IL-4-mediated signaling pathway. It binds IL4RA to initiate JAK/STAT6 signaling cascades that drive Th2 differentiation, IgE class switching, and other downstream effects. This is a core biological process for IL-4. Reason: This is the most specific and appropriate BP term for IL-4 as the initiating ligand of this pathway. The IBA annotation is phylogenetically well-supported and represents the central biological role of the protein. Extensively documented in the deep research and UniProt function annotation. Supporting Evidence: file:human/IL4/IL4-deep-research-falcon.md IL-4 signals via two receptor complexes...type I (IL-4R-alpha/gamma-c) largely on hematopoietic cells and type II (IL-4R-alpha/IL-13R-alpha1) on many non-hematopoietic cells. JAK-STAT is canonical...converging on STAT6 PMID:12574355 IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway |
| GO:0045893 positive regulation of DNA-templated transcription | IBA GO_REF:0000033 | ACCEPT | Summary: IL-4 signaling via STAT6 activates transcription of numerous target genes including GATA3, germline Ig epsilon transcripts, CD23, and MHC class II genes. This is a well-established downstream consequence of IL-4 signaling. Reason: IL-4 is well-documented as a transcriptional activator through STAT6-mediated signaling. The IBA annotation is broadly correct and represents a core downstream activity. This is a general term but appropriate for a cytokine with pleiotropic transcriptional effects. Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling PMID:20554961 IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor |
| GO:0050776 regulation of immune response | IBA GO_REF:0000033 | ACCEPT | Summary: IL-4 is a major immunoregulatory cytokine that shapes adaptive immune responses by driving Th2 polarization, B cell activation and class switching, and M2 macrophage polarization, while simultaneously suppressing Th1 responses. Reason: This is a broad but accurate term for IL-4. As a key immunoregulatory cytokine, IL-4 fundamentally regulates immune responses. The IBA annotation is well-supported. While more specific terms exist and are also annotated, this general term appropriately captures the broad immunoregulatory role. Supporting Evidence: file:human/IL4/IL4-deep-research-falcon.md IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic) across airway and barrier diseases |
| GO:0050728 negative regulation of inflammatory response | IBA GO_REF:0000033 | ACCEPT | Summary: IL-4 has well-documented anti-inflammatory properties, particularly in suppressing pro-inflammatory Th1/M1 macrophage responses, inhibiting TNF-alpha production, and promoting M2 (anti-inflammatory) macrophage polarization. This is a core function of IL-4 in immune regulation. Reason: IL-4 is a canonical anti-inflammatory cytokine that promotes M2 macrophage polarization and suppresses pro-inflammatory cytokine production. The IBA annotation is phylogenetically well-supported and consistent with extensive experimental evidence. Supporting Evidence: file:human/IL4/IL4-deep-research-falcon.md IL-4 drives...alternative (M2) macrophage activation |
| GO:0005125 cytokine activity | IEA GO_REF:0000043 | ACCEPT | Summary: IL-4 is by definition a cytokine - a secreted signaling molecule that modulates immune cell behavior. This is the most fundamental molecular function classification for IL-4. Reason: IL-4 is unambiguously a cytokine. The IEA annotation from UniProt keyword mapping is correct and consistent with the IDA annotation for the same term. This broad MF term is appropriate alongside the more specific GO:0005136 (interleukin-4 receptor binding). Supporting Evidence: file:human/IL4/IL4-uniprot.txt Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation |
| GO:0005126 cytokine receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: IL-4 binds cytokine receptors (IL4RA, IL13RA1) as part of its signaling mechanism. This is a parent term of the more specific GO:0005136 (interleukin-4 receptor binding). Reason: This is a correct but less specific parent term. Since the more specific GO:0005136 is also annotated, this IEA annotation is redundant but not incorrect. Acceptable as an IEA capturing the broader category. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Upon binding to IL4, IL4R receptor dimerizes either with the common IL2R gamma chain/IL2RG...or with the IL13RA1 |
| GO:0005136 interleukin-4 receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: IL-4 specifically binds the IL-4 receptor alpha chain (IL4RA) at its site I interface (helices A-C, key residues Glu9/Arg88). This is the most specific and informative MF term for IL-4. Reason: This is the core molecular function of IL-4 as a ligand. The IEA annotation from InterPro domain mapping is correct and supported by extensive structural and biochemical data, including crystal structures of the IL-4/IL4RA complex. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Interacts with IL4R...Interacts with IL13RA1 file:human/IL4/IL4-deep-research-falcon.md structure-function mapping identifies site I on helices A-C as the IL-4R-alpha interface (key residues Glu9, Arg88) |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: IL-4 is a secreted cytokine that functions in the extracellular region. UniProt annotates it as Secreted. Reason: IL-4 is a secreted protein with a signal peptide (residues 1-24). The extracellular region localization is correct and well-established. This is broader than GO:0005615 (extracellular space) but acceptable as an IEA annotation. Supporting Evidence: file:human/IL4/IL4-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005615 extracellular space | IEA GO_REF:0000043 | ACCEPT | Summary: IL-4 is secreted into the extracellular space where it functions as a paracrine/ autocrine signaling molecule. Reason: Correct IEA annotation consistent with the IDA evidence for the same term. IL-4 is a secreted cytokine that acts in the extracellular space. Supporting Evidence: file:human/IL4/IL4-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: IL-4 is a key mediator of immune responses, particularly type 2 immunity. This is a very broad BP term. Reason: This is a very general but correct IEA annotation. IL-4 is fundamentally an immune response mediator. More specific terms are also annotated. Acceptable as a broad IEA classification. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses |
| GO:0008083 growth factor activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IL-4 was historically known as B-cell stimulatory factor 1 (BSF-1) and promotes proliferation of B and T cells. However, its primary identity is as a cytokine rather than a classical growth factor. Reason: While IL-4 does promote cell proliferation (B cells, T cells), its primary molecular function is better described as cytokine activity (GO:0005125) and IL-4 receptor binding (GO:0005136). Growth factor activity is a secondary characterization. The UniProt keyword mapping that generated this annotation reflects the historical BSF-1 naming but is not the most informative descriptor. Supporting Evidence: file:human/IL4/IL4-uniprot.txt AltName...B-cell stimulatory factor 1; Short=BSF-1 |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000117 | ACCEPT | Summary: IL-4 upregulates expression of numerous genes through STAT6 signaling, including GATA3, AID, germline Ig epsilon transcripts, CD23, and MHC class II molecules. Reason: This is a broad but correct IEA annotation from ARBA. IL-4 is a potent inducer of gene expression in immune cells. More specific transcription regulation terms are also annotated. Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IL-4 can promote cell migration in certain contexts, including macrophage and tumor cell migration. This is a secondary, context-dependent effect. Reason: While there is evidence that IL-4 can regulate cell migration, this is not a core function of the cytokine. It represents a pleiotropic downstream effect rather than the primary evolved function. The ARBA-generated IEA annotation is acceptable but should not be considered a defining function. |
| GO:0042113 B cell activation | IEA GO_REF:0000043 | ACCEPT | Summary: IL-4 is a major B cell activating factor that induces B cell proliferation, class switching to IgE and IgG, and upregulation of MHC class II and CD23. This is one of the historically defining functions of IL-4 (originally named B-cell stimulatory factor 1). Reason: B cell activation is a core function of IL-4. The IEA from UniProt keyword mapping accurately reflects that IL-4 was originally identified as BSF-1 precisely because of its B cell activating properties. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Induces the expression of class II MHC molecules on resting B-cells. Enhances both secretion and cell surface expression of IgE and IgG1 |
| GO:0045321 leukocyte activation | IEA GO_REF:0000117 | ACCEPT | Summary: IL-4 activates multiple leukocyte types including B cells, T cells, macrophages, and dendritic cells. This is a broad parent term. Reason: This broad IEA term is correct. IL-4 activates multiple leukocyte populations. More specific child terms (B cell activation, T cell activation, macrophage activation) are also annotated. |
| GO:0051239 regulation of multicellular organismal process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IL-4 regulates immune processes at the organismal level, affecting allergic responses, anti-helminth immunity, and tissue remodeling. Reason: This is an extremely broad and uninformative term. While technically true, it provides no useful information about IL-4 function. More specific terms are available and annotated. The ARBA machine learning annotation is too general to be informative. |
| GO:0080090 regulation of primary metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IL-4 can regulate metabolic processes in target cells, but this is an extremely broad and uninformative annotation. Reason: This term is far too general to be informative for IL-4 annotation. While IL-4 signaling does affect metabolic processes in target cells, this ARBA-generated term does not convey any meaningful biological insight about the protein. |
| GO:0005515 protein binding | IPI PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... | MODIFY | Summary: PMID:10219247 reports the crystal structure of IL-4 in complex with IL4RA at 2.30 angstroms resolution, demonstrating direct protein-protein interaction. The WITH column specifies UniProtKB:P24394 (IL4R). Reason: The protein binding annotation is uninformative. The interaction demonstrated in PMID:10219247 is specifically IL-4 binding to the IL-4 receptor alpha chain, which is better captured by GO:0005136 (interleukin-4 receptor binding), which is already annotated via IEA, TAS, and IDA evidence. Proposed replacements: interleukin-4 receptor binding Supporting Evidence: PMID:10219247 IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP) file:human/IL4/IL4-uniprot.txt X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 25-153 IN COMPLEX WITH IL4R...INTERACTION WITH IL4R |
| GO:0005515 protein binding | IPI PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... | MODIFY | Summary: PMID:18243101 reports the crystal structure of IL-4 in complex with IL13RA1 and IL4RA, elucidating the molecular basis of cytokine receptor pleiotropy in the IL-4/IL-13 system. The GOA TSV shows two separate annotations from this PMID, one with IL4R (P24394) and one with IL13RA1 (P78552). Reason: The generic protein binding term is uninformative. The interaction with IL4RA is better captured by GO:0005136, and the interaction with IL13RA1 represents a component of the type II receptor complex formation. Proposed replacements: interleukin-4 receptor binding Supporting Evidence: PMID:18243101 Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes file:human/IL4/IL4-uniprot.txt X-RAY CRYSTALLOGRAPHY (2.93 ANGSTROMS) OF 25-153...INTERACTION WITH IL13RA1, AND FUNCTION |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | MODIFY | Summary: PMID:23597562 is about a small-molecule FGFR inhibitor (SSR128129E) and its anti-tumor angiogenesis effects. The WITH column specifies IL4R (P24394). This annotation likely derives from an IntAct high-throughput dataset associated with this publication where IL4-IL4R interaction was detected. Reason: The IL-4/IL-4R interaction is well-established but the generic protein binding term is uninformative. If the interaction is genuine, it is better captured by GO:0005136 (interleukin-4 receptor binding). Additionally, the primary publication focus is FGFR biology, making the provenance of this specific annotation unclear. Proposed replacements: interleukin-4 receptor binding Supporting Evidence: PMID:23597562 we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling |
| GO:0005515 protein binding | IPI PMID:8266078 Interleukin-2 receptor gamma chain: a functional component o... | MODIFY | Summary: PMID:8266078 demonstrates that the IL-2 receptor gamma chain is a functional component of the IL-4 receptor, showing IL-4 binding and signaling through the IL4RA/IL2RG complex. Reason: As with the other protein binding annotations for IL-4, the interaction with IL4R is better captured by the specific term GO:0005136 (interleukin-4 receptor binding). The generic protein binding term is uninformative. Proposed replacements: interleukin-4 receptor binding Supporting Evidence: PMID:8266078 IL-2R gamma was demonstrated to be a component of the IL-4 receptor on the basis of chemical cross-linking data, the ability of IL-2R gamma to augment IL-4 binding affinity, and the requirement for IL-2R gamma in IL-4-mediated phosphorylation of insulin receptor substrate-1 |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IDA PMID:23103943 Redirecting cell-type specific cytokine responses with engin... | ACCEPT | Summary: IL-4 signals through JAK1/JAK3 (type I receptor) and JAK1/TYK2 (type II receptor) to activate STAT6, and to a lesser extent STAT3. This annotation captures the canonical signaling mechanism. Reason: JAK-STAT signaling is the primary intracellular signaling pathway activated by IL-4. The IDA annotation from ComplexPortal is well-supported by extensive literature. Supporting Evidence: PMID:23103943 Formation of the IL-4/IL-4RΞ±/Ξ³c or IL-4/IL-4RΞ±/IL-13RΞ±1 complex on the cell surface activates intracellular signaling pathways including the Jak-STAT and the PI3K/Akt pathways file:human/IL4/IL4-uniprot.txt Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6 file:human/IL4/IL4-deep-research-falcon.md JAK-STAT is canonical...type I (primarily JAK1/JAK3) and type II (JAK2/TYK2 reported), converging on STAT6 |
| GO:0035771 interleukin-4-mediated signaling pathway | NAS PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... | ACCEPT | Summary: PMID:18243101 elucidated the structural basis for cytokine receptor pleiotropy in the IL-4/IL-13 system, providing mechanistic insight into IL-4 signaling through both type I and type II receptor complexes. Reason: This NAS annotation is well-supported. The referenced paper provides definitive structural evidence for IL-4 receptor complex assembly, which is the initiating event of the IL-4-mediated signaling pathway. Duplicate of the IBA annotation but with different evidence, which is acceptable. Supporting Evidence: PMID:18243101 Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes file:human/IL4/IL4-uniprot.txt X-RAY CRYSTALLOGRAPHY...OF 25-153, DISULFIDE BONDS, INTERACTION WITH IL13RA1, AND FUNCTION |
| GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein | NAS PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... | ACCEPT | Summary: IL-4 receptor engagement leads to JAK-mediated phosphorylation of STAT6 (at Y641) and STAT3 (at Y705). This is a direct mechanistic consequence of IL-4 signaling. Reason: STAT6 tyrosine phosphorylation is the key signaling event downstream of IL-4 receptor activation. The NAS annotation from ComplexPortal accurately captures this core signaling mechanism. The Reactome pathway also documents JAK1 phosphorylation of STAT3 and STAT6. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6 PMID:12574355 IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway |
| GO:1902107 positive regulation of leukocyte differentiation | NAS PMID:23103943 Redirecting cell-type specific cytokine responses with engin... | ACCEPT | Summary: IL-4 drives differentiation of multiple leukocyte lineages including Th2 cells from naive T cells, dendritic cells from monocytes, and M2 macrophages from monocytes/ macrophages. Reason: This is a well-supported annotation. IL-4 is a key driver of leukocyte differentiation programs, particularly Th2 differentiation and dendritic cell differentiation. The NAS evidence from ComplexPortal is consistent with extensive experimental data. Supporting Evidence: PMID:23103943 Cytokines dimerize their receptors, with the binding of the 'second chain' triggering signaling file:human/IL4/IL4-deep-research-falcon.md IL-4 drives Th2 differentiation (via STAT6->GATA3), B-cell proliferation and class-switch recombination to IgE, and alternative (M2) macrophage activation |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IGI PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... | ACCEPT | Summary: PMID:12574355 demonstrates that IL-4 induces AID expression via JAK/STAT6 signaling, and that CD45 negatively regulates this pathway by acting as a JAK phosphatase. The IGI annotation with STAT6 (P42226) provides genetic interaction evidence. Reason: The paper directly demonstrates IL-4 activates JAK/STAT6 signaling using dominant- negative STAT6 experiments. The genetic interaction with STAT6 provides strong evidence for this pathway annotation. Supporting Evidence: PMID:12574355 IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway |
| GO:0035771 interleukin-4-mediated signaling pathway | IDA PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... | ACCEPT | Summary: PMID:12574355 directly demonstrates IL-4 signaling through JAK/STAT6 in the context of AID gene induction in B cells. Reason: The paper provides direct experimental evidence for IL-4-mediated signaling pathway activation using IL-4 stimulation of B cells and demonstrating JAK-dependent STAT6 activation. Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines...IL-4-induced AID expression was further enhanced by CD40 signaling |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... | ACCEPT | Summary: PMID:12574355 shows IL-4 induces AID gene transcription through STAT6-dependent mechanisms. The IGI evidence includes interactions with CD45 (P08575), CD40 (P29965), and STAT6 (P42226). Reason: The paper demonstrates IL-4 positively regulates transcription of the AID gene in B cells, with genetic interaction evidence from STAT6 dominant-negative, CD45, and CD40 experiments. Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling |
| GO:0005125 cytokine activity | IDA PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... | ACCEPT | Summary: PMID:10219247 reports the crystal structure of the IL-4/IL4RA complex and characterizes the receptor binding interface, providing direct structural evidence for IL-4's cytokine activity. Reason: This IDA annotation is well-supported. The referenced paper demonstrates direct IL-4/receptor interaction through structural analysis, confirming IL-4 functions as a cytokine that binds and activates its cognate receptor. Supporting Evidence: PMID:10219247 Interleukin-4 (IL-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma file:human/IL4/IL4-uniprot.txt Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface |
| GO:0005615 extracellular space | IDA PMID:3279117 Modulation of phenotypic and functional properties of human ... | ACCEPT | Summary: PMID:3279117 demonstrates that exogenous recombinant IL-4 acts on monocytes in culture, confirming its activity as a secreted extracellular protein. The paper shows IL-4 modulates monocyte phenotype and function when added to culture medium. Reason: IL-4 is a secreted cytokine with a signal peptide. Its localization to the extracellular space is unambiguous. The paper demonstrates IL-4 acting as an extracellular factor on monocytes. Supporting Evidence: PMID:3279117 Highly purified peripheral blood monocytes were cultured in the presence of rIL-4 file:human/IL4/IL4-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0035771 interleukin-4-mediated signaling pathway | IDA PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... | ACCEPT | Summary: PMID:10219247 provides structural evidence for IL-4 receptor complex formation, the initiating event of the IL-4-mediated signaling pathway. Reason: The crystal structure of IL-4 bound to IL4RA demonstrates the molecular basis of IL-4 signaling initiation. This IDA annotation is well-supported and consistent with other annotations for the same GO term. Supporting Evidence: PMID:10219247 this intermediate complex recruits the common gamma chain (gamma c), thereby initiating transmembrane signaling file:human/IL4/IL4-uniprot.txt Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:11967989 Interleukin-4 regulates connective tissue growth factor expr... | KEEP AS NON CORE | Summary: PMID:11967989 shows that IL-4 attenuates TGF-beta-stimulated induction of CTGF mRNA expression in human lung fibroblasts, through interference with TGF-beta-induced transcriptional activation of the CTGF gene. Reason: The paper demonstrates IL-4 can negatively regulate specific gene transcription (CTGF), but this is a context-specific effect in lung fibroblasts rather than a core function of IL-4. IL-4's primary role is transcriptional activation of immune genes, not transcriptional repression. Supporting Evidence: PMID:11967989 IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA expression by 50%...IL-4 interfered with the TGF-beta-induced transcriptional activation of the CTGF gene |
| GO:1903845 negative regulation of cellular response to transforming growth factor beta stimulus | IDA PMID:11967989 Interleukin-4 regulates connective tissue growth factor expr... | KEEP AS NON CORE | Summary: PMID:11967989 directly demonstrates that IL-4 antagonizes TGF-beta signaling in lung fibroblasts by attenuating TGF-beta-induced CTGF expression. Reason: While the paper provides direct evidence for this annotation, IL-4's antagonism of TGF-beta signaling in fibroblasts is a tissue-specific context-dependent effect, not a core function of the cytokine. This represents pleiotropic activity. Supporting Evidence: PMID:11967989 IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA expression by 50%. This effect was selective because IL-4 did not affect fibronectin or alpha1(I) collagen mRNA expression induced by TGF-beta |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:31432141 miRβ320a upregulation contributes to the development of pree... | KEEP AS NON CORE | Summary: PMID:31432141 identifies IL-4 as a direct target of miR-320a in trophoblast cells (HTR-8/SVneo). Rescue experiments demonstrate that IL-4 overexpression partially reverses the anti-proliferative effect of miR-320a on trophoblast cells (MTT assay). The IGI evidence involves miR-320a (RNAcentral:URS00003CF1AD_9606) with acts_upstream_of_or_within qualifier. The proliferation effect is in trophoblast cells in the context of preeclampsia. Reason: The paper provides evidence that IL-4 promotes trophoblast cell proliferation in the preeclampsia context. While IL-4 also promotes B and T cell proliferation as a core function (annotated separately via ISS), this specific annotation reflects a non-immune cell proliferation effect that is not a core function of the cytokine. Supporting Evidence: PMID:31432141 restoring the expression level of IL-4 partially decreased the inhibitory effect of miR-320a overexpression on HTR-8/SVneo cell proliferation PMID:31432141 Collectively, the present data suggested that IL-4 was a functional target gene of miR-320a, and miR-320a upregulation inhibited the proliferation and invasion of HTR-8/SVneo cells by directly targeting IL-4 |
| GO:0030335 positive regulation of cell migration | IGI PMID:31432141 miRβ320a upregulation contributes to the development of pree... | KEEP AS NON CORE | Summary: PMID:31432141 studies miR-320a in preeclampsia trophoblast cells (HTR-8/SVneo). IL-4 is identified as a direct target of miR-320a. Rescue experiments show that overexpression of IL-4 partially reverses the inhibitory effect of miR-320a on trophoblast cell invasion (Transwell assay). The IGI evidence involves miR-320a (RNAcentral:URS00003CF1AD_9606) as the interacting partner, with acts_upstream_of_or_within qualifier. The cell migration/invasion effect is in trophoblast cells, not immune cells. Reason: The paper provides evidence that IL-4 promotes trophoblast cell invasion in the context of preeclampsia, which is consistent with the IEA annotation for the same term that was already marked KEEP_AS_NON_CORE. Cell migration promotion is not a core immune function of IL-4 but represents a pleiotropic effect in non-immune cell types. Supporting Evidence: PMID:31432141 overexpression of IL-4 in HTR-8/SVneo cells reduced the inhibitory effect of miR-320a overexpression on cell invasion PMID:31432141 miR-320a upregulation inhibited the proliferation and invasion of HTR-8/SVneo cells by directly targeting IL-4 |
| GO:0032733 positive regulation of interleukin-10 production | IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... | ACCEPT | Summary: PMID:30634164 studies macrophage polarization and shows that M2 macrophages (induced by IL-4 and IL-13) express higher levels of IL-10 than M1 macrophages. The IGI evidence involves IL-13 (P35225), reflecting the cooperative use of IL-4 and IL-13 in M2 polarization protocols. Reason: The paper demonstrates that IL-4/IL-13-induced M2 macrophages express higher IL-10 levels than M1 macrophages, supporting IL-4's role in promoting IL-10 production. This is consistent with IL-4's well-established anti-inflammatory M2-polarizing function and the known IL-10 production by M2 macrophages. Supporting Evidence: PMID:30634164 M1 macrophages express higher levels of IL-16 than M2 macrophages but express lower levels of IL-10 and mir-145 than M2 cells |
| GO:0042116 macrophage activation | IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... | ACCEPT | Summary: PMID:30634164 uses IL-4 and IL-13 to induce M2 macrophage polarization from THP-1 monocytes. IL-4 is a canonical driver of alternative macrophage activation (M2 polarization). The IGI evidence with IL-13 (P35225) reflects the cooperative use of these cytokines in M2 polarization. Reason: M2 macrophage activation by IL-4 is one of its best-established functions. The paper directly uses IL-4 in the M2 polarization protocol. This is extensively documented in the deep research and is a core function of IL-4 in innate immunity. Supporting Evidence: PMID:30634164 THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation) file:human/IL4/IL4-deep-research-falcon.md IL-4 drives...alternative (M2) macrophage activation; IL-13 overlaps but acts more directly on structural cells |
| GO:0050728 negative regulation of inflammatory response | IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... | ACCEPT | Summary: PMID:30634164 demonstrates that IL-4/IL-13-induced M2 macrophages have an anti-inflammatory profile with high IL-10 and low pro-inflammatory cytokines. IL-4 suppresses inflammatory responses through M2 macrophage polarization. The IGI evidence with IL-13 (P35225) reflects cooperative anti-inflammatory signaling. Reason: This is a duplicate of the IBA annotation for the same term, with independent IGI evidence. The anti-inflammatory role of IL-4 is well-established and represents a core function. Duplicate annotations with different evidence codes are acceptable. Supporting Evidence: PMID:30634164 THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation) file:human/IL4/IL4-deep-research-falcon.md IL-4 drives...alternative (M2) macrophage activation |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 upregulates gene expression in target cells through STAT6-mediated transcriptional activation. Transferred from mouse IL-4 (P07750) and rat IL-4 (P20096). Reason: This ISS annotation is well-supported by the conserved function of IL-4 across mammals. IL-4 is a potent inducer of gene expression through STAT6 signaling. The annotation is consistent with the IDA evidence for transcription regulation and with the IEA annotation for the same term. Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines |
| GO:0150076 neuroinflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has been implicated in neuroinflammation, particularly in the context of neuroprotection and microglial polarization. Transferred from mouse IL-4 (P20096) by ARUK-UCL curators. Reason: While IL-4 has documented roles in neuroinflammation (primarily anti-inflammatory/ neuroprotective effects via M2 microglial polarization), this is a tissue-specific context-dependent activity, not a core immune function of IL-4. The ISS from mouse is reasonable but this represents a specialized function. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 suppresses TNF-alpha production, particularly in macrophages, as part of its anti-inflammatory and M2-polarizing activity. Transferred from mouse IL-4 (P07750). Reason: Suppression of TNF-alpha production is a well-established function of IL-4 in the context of its anti-inflammatory M2 macrophage polarization program. The ISS from mouse is appropriate given conserved IL-4 function. Supporting Evidence: file:human/IL4/IL4-deep-research-falcon.md IL-4 drives...alternative (M2) macrophage activation |
| GO:1901857 positive regulation of cellular respiration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has been reported to promote mitochondrial respiration in macrophages as part of M2 metabolic reprogramming. Transferred from mouse IL-4 (P07750) by ARUK-UCL. Reason: While IL-4-driven M2 macrophage polarization involves metabolic reprogramming toward oxidative phosphorylation, this metabolic effect is a downstream consequence of M2 polarization rather than a core function of IL-4 itself. The annotation is not incorrect but represents a specialized downstream effect. |
| GO:2001171 positive regulation of ATP biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Related to the metabolic reprogramming of M2 macrophages toward oxidative phosphorylation. Transferred from mouse IL-4 (P07750) by ARUK-UCL. Reason: This is a highly specific metabolic effect that is downstream of M2 macrophage polarization. Not a core function of IL-4 as a cytokine. Over-specific annotation of a downstream metabolic consequence. |
| GO:0150079 negative regulation of neuroinflammatory response | IC GO_REF:0000111 | KEEP AS NON CORE | Summary: IC annotation inferred from ISS evidence. IL-4 has anti-inflammatory effects in the CNS, promoting M2 microglial polarization and suppressing neuroinflammation. Reason: While IL-4 has documented neuroprotective and anti-neuroinflammatory effects, these are tissue-specific activities rather than core immune functions. The IC evidence based on ISS is reasonable but this represents a specialized function. |
| GO:0048260 positive regulation of receptor-mediated endocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 may promote receptor-mediated endocytosis in certain cell types, possibly related to amyloid-beta clearance by microglia. Transferred from mouse IL-4 (P07750 and P20096) by ARUK-UCL. Reason: This annotation likely relates to IL-4's role in promoting microglial phagocytic clearance of amyloid-beta, which is a very specialized neuroimmune function rather than a core IL-4 activity. |
| GO:1900223 positive regulation of amyloid-beta clearance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has been reported to promote amyloid-beta clearance by microglia in Alzheimer's disease models. Transferred from mouse IL-4 (P07750 and P20096) by ARUK-UCL. Reason: While there is mouse literature supporting IL-4's role in promoting amyloid-beta clearance, this is a highly specialized neuroimmune function that is far from the core evolved function of IL-4 as an immune cytokine. The ISS transfer is reasonable but this represents a tissue-specific activity. |
| GO:0016239 positive regulation of macroautophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has been reported to stimulate autophagy in dendritic cells. The UniProt function annotation notes IL-4 stimulates autophagy by interfering with mTORC1 signaling and through RUFY4 induction. Transferred from mouse IL-4 (P07750). Reason: While UniProt documents this function, autophagy induction is a specialized downstream effect of IL-4 signaling rather than a core function. The ISS annotation is supported by the UniProt function description. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4 |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:24906148 Eosinophils and type 2 cytokine signaling in macrophages orc... | KEEP AS NON CORE | Summary: PMID:24906148 demonstrates that IL-4/IL-13 signaling in macrophages is required for cold-induced beige fat biogenesis. Administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity. The ISS is from mouse IL-4 (P07750). Reason: While the paper provides compelling evidence that IL-4 promotes beige fat thermogenesis through alternatively activated macrophages, this is a specialized metabolic function far removed from IL-4's core immune role. Supporting Evidence: PMID:24906148 Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat PMID:24906148 administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity |
| GO:0042110 T cell activation | IGI PMID:18337562 CCL5-mediated T-cell chemotaxis involves the initiation of m... | UNDECIDED | Summary: PMID:18337562 is about CCL5-mediated T cell chemotaxis involving mTOR/4E-BP1 translation initiation. The paper studied CD4+ T cell migration in response to CCL5, not IL-4. The IGI evidence involves CD82 (P10747). The connection to IL-4 is unclear. Reason: The referenced publication (PMID:18337562) is about CCL5 (RANTES)-mediated T cell chemotaxis, not IL-4 function. While IL-4 is known to activate T cells (particularly driving Th2 differentiation), this specific annotation appears to reference an unrelated paper. The annotation may have been made based on a secondary finding or data in the paper, but the primary focus is CCL5. Supporting Evidence: PMID:18337562 CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1 |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:16606666 B7-H4 expression identifies a novel suppressive macrophage p... | KEEP AS NON CORE | Summary: PMID:16606666 demonstrates that IL-4 inhibits B7-H4 (VTCN1) expression on tumor macrophages in human ovarian carcinoma. IL-4 negatively regulates B7-H4 transcription, in contrast to IL-6 and IL-10 which stimulate its expression. Reason: The paper provides direct evidence that IL-4 negatively regulates B7-H4 expression on macrophages. This is consistent with the other GO:0045892 annotation from PMID:18579517 (also KEEP_AS_NON_CORE) and the GO:0000122 annotation from PMID:11967989 for CTGF. IL-4's ability to repress specific genes is a real but context-dependent activity, not a core function. Supporting Evidence: PMID:16606666 granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6785821 | ACCEPT | Summary: Reactome annotation for IL-4 participation in the IL-4/IL-13 signaling pathway, specifically the SOCS5/SOCS1 binding to IL4RA reaction. IL-4 is correctly placed in the extracellular region. Reason: IL-4 is a secreted cytokine in the extracellular region. These Reactome TAS annotations correctly reflect IL-4's participation in signaling pathway reactions as an extracellular ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786058 | ACCEPT | Summary: Reactome annotation for IL-4 signaling - JAK1 binding to IL4R in IL4-bound complex. Reason: Duplicate CC annotation from Reactome pathway. IL-4 is correctly localized to the extracellular region as part of the receptor-ligand complex. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786070 | ACCEPT | Summary: Reactome annotation for type II receptor complex assembly (IL-4 complex binding IL13RA1/TYK2). Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786072 | ACCEPT | Summary: Reactome annotation for STAT3/STAT6 dissociation step in IL-4 signaling. Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786092 | ACCEPT | Summary: Reactome annotation for type I receptor complex assembly (IL-4 complex binding IL2RG/JAK3). Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786095 | ACCEPT | Summary: Reactome annotation for JAK1 phosphorylation of STAT3/STAT6 in IL-4 signaling. Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786096 | ACCEPT | Summary: Reactome annotation for phosphorylation of IL4R/IL2RG/JAK1 components. Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786101 | ACCEPT | Summary: Reactome annotation for IL-4 binding to IL4R/JAK2. Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6786124 | ACCEPT | Summary: Reactome annotation for STAT3/STAT6 binding to phosphorylated IL4R. Reason: Duplicate CC annotation from Reactome pathway. Correct localization. |
| GO:0043011 myeloid dendritic cell differentiation | IDA PMID:16116184 Galectin-9 induces maturation of human monocyte-derived dend... | ACCEPT | Summary: PMID:16116184 studies galectin-9 effects on monocyte-derived dendritic cells that were generated using the standard IL-4 + GM-CSF protocol. The paper uses IL-4 to differentiate monocytes into immature DCs, which are then matured by galectin-9. Reason: IL-4 is a well-established driver of dendritic cell differentiation from monocytes. The paper directly employs IL-4 in the DC differentiation protocol. The IL-4 + GM-CSF system for DC generation is one of the most widely used in immunology. Supporting Evidence: PMID:16116184 Gal-9 had no or little effect on differentiation of human monocytes into immature DCs |
| GO:1903660 negative regulation of complement-dependent cytotoxicity | IMP PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell... | KEEP AS NON CORE | Summary: PMID:16034134 demonstrates that IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement through PI3K/Akt signaling. Reason: The paper provides direct evidence that IL-4 protects endothelial cells from complement-mediated killing via PI3K/Akt pathway activation. This is a specialized cytoprotective effect in the xenotransplantation context, not a core immune function of IL-4. Supporting Evidence: PMID:16034134 porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IMP PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell... | KEEP AS NON CORE | Summary: PMID:16034134 demonstrates that IL-4 protects porcine endothelial cells from apoptosis induced by TNF-alpha plus cycloheximide through PI3K/Akt signaling. Reason: The paper provides direct evidence that IL-4 protects endothelial cells from apoptosis via PI3K/Akt pathway activation. This represents a cytoprotective effect consistent with IL-4's known anti-apoptotic signaling but in a non-immune cell context. Supporting Evidence: PMID:16034134 IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway |
| GO:0010633 negative regulation of epithelial cell migration | IDA PMID:11698262 Lung epithelial barrier function and wound healing are decre... | KEEP AS NON CORE | Summary: PMID:11698262 demonstrates that IL-4 and IL-13 decrease wound healing and migration in Calu-3 human lung epithelial cells. IL-4 treatment decreased cell migration in wound-healing assays on collagen I. Reason: The paper provides direct evidence that IL-4 inhibits epithelial cell migration in lung epithelial cells. This is a tissue-specific effect on non-immune cells in the context of airway epithelial barrier function and wound healing, representing a pleiotropic activity rather than a core immune function. Supporting Evidence: PMID:11698262 In wound-healing assays of cells grown on collagen I, IL-4 and IL-13 decreased migration, whereas IFN-gamma treatment enhanced migration, compared with control cells |
| GO:0097028 dendritic cell differentiation | IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ... | ACCEPT | Summary: PMID:21149635 demonstrates that monocytic cells derived from human embryonic stem cells differentiate through pathways involving IL-4, with M2-like macrophage characteristics. Reason: IL-4 is well-established as a key factor in dendritic cell differentiation from monocyte precursors. The paper studies monocyte differentiation pathways including IL-4 dependent steps. This is consistent with the GO:0043011 annotation. Supporting Evidence: PMID:21149635 monocytic cells derived from human embryonic stem cells (hESCs) and from fetal liver follow a differentiation pathway different to that of adult cells |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:19346497 IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses... | ACCEPT | Summary: PMID:19346497 studies IFN-lambda1 inhibition of GATA3 and Th2 responses. The paper demonstrates IL-4-driven transcription in the context of Th2 cytokine gene expression. IL-4 stimulation leads to GATA3 expression and IL-4Ralpha upregulation, both of which are transcription-dependent processes. Reason: IL-4 is a potent inducer of gene transcription through STAT6 signaling. This IDA annotation is consistent with multiple other annotations for the same term and with the known biology of IL-4. Supporting Evidence: PMID:19346497 Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation |
| GO:0032736 positive regulation of interleukin-13 production | IDA PMID:19346497 IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses... | ACCEPT | Summary: PMID:19346497 demonstrates that IL-4-driven Th2 responses include IL-13 production, which is suppressed by IFN-lambda1. The paper shows IL-4 promotes IL-13 expression as part of the Th2 cytokine program. Reason: IL-4 and IL-13 are co-regulated Th2 cytokines. IL-4-driven Th2 differentiation via GATA3 leads to increased IL-13 production as part of the Th2 cytokine program. The paper directly demonstrates this relationship. Supporting Evidence: PMID:19346497 Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation file:human/IL4/IL4-deep-research-falcon.md IL-4 drives Th2 differentiation (via STAT6->GATA3) |
| GO:0045582 positive regulation of T cell differentiation | IDA PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... | ACCEPT | Summary: PMID:20554961 studies IL-4-driven Th2 differentiation and how type I IFN opposes it. IL-4 promotes Th2 development by inducing GATA3. Reason: IL-4 is the canonical driver of Th2 cell differentiation from naive T cells. The paper directly studies this process and demonstrates IL-4-dependent GATA3 induction as the key mechanism of Th2 commitment. Supporting Evidence: PMID:20554961 IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor, and the Th2 phenotype is stabilized by a GATA3-dependent auto-regulatory loop |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... | ACCEPT | Summary: PMID:20554961 demonstrates that IL-4 promotes transcription of GATA3 through STAT6 signaling as part of Th2 commitment. Reason: The paper provides direct evidence that IL-4 activates GATA3 transcription through STAT6, consistent with the known transcription-activating function of IL-4. Supporting Evidence: PMID:20554961 IL-4 receptor signaling promotes STAT6 recruitment and phosphorylation... which ultimately regulates induction of GATA3 transcription |
| GO:2000553 positive regulation of T-helper 2 cell cytokine production | IDA PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... | ACCEPT | Summary: PMID:20554961 demonstrates that IL-4 promotes Th2 cytokine production by driving GATA3-dependent Th2 differentiation and cytokine gene expression. Reason: IL-4-driven Th2 differentiation leads to increased production of Th2 cytokines (IL-4, IL-5, IL-13). This is a core function of IL-4 as the master Th2-polarizing cytokine. Supporting Evidence: PMID:20554961 IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:18579517 LEF-1 negatively controls interleukin-4 expression through a... | KEEP AS NON CORE | Summary: PMID:18579517 demonstrates that IL-4 stimulation negatively regulates expression of LEF-1 and TCF-1 transcription factors in primary T cells, creating a positive feedback loop that reinforces IL-4 gene expression by removing transcriptional repressors. This represents IL-4 negatively regulating transcription of specific target genes (LEF-1, TCF-1). Reason: The paper provides direct evidence that IL-4 downregulates LEF-1 and TCF-1 expression, which are Wnt pathway transcription factors. This is consistent with the existing KEEP_AS_NON_CORE annotation for GO:0000122 (negative regulation of transcription by RNA polymerase II) from PMID:11967989 for CTGF. IL-4's ability to repress specific genes is a real but secondary function compared to its primary role as a transcriptional activator through STAT6. Supporting Evidence: PMID:18579517 we found that IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:18579517 LEF-1 negatively controls interleukin-4 expression through a... | ACCEPT | Summary: PMID:18579517 demonstrates that IL-4 positively regulates its own gene expression through a feedback mechanism. IL-4 stimulation suppresses LEF-1 and TCF-1, which are negative regulators of the IL-4 promoter. Knockdown of LEF-1 by siRNA increased IL-4 mRNA expression, confirming that LEF-1 is a transcriptional repressor of IL-4. By removing this repression, IL-4 indirectly promotes transcription of IL-4 and potentially other Th2 cytokine genes. Reason: The paper provides evidence that IL-4 positively regulates transcription through a feedback loop involving suppression of LEF-1/TCF-1 transcriptional repressors. This is consistent with the other ACCEPT annotations for GO:0045893 from IBA, IDA (PMID:19346497, PMID:20554961), which all document IL-4's well-established role as a transcriptional activator via STAT6 signaling. Supporting Evidence: PMID:18579517 Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression PMID:18579517 we found that IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression |
| GO:0008203 cholesterol metabolic process | ISS PMID:11971948 Interleukin-4 deficiency promotes gallstone formation. | KEEP AS NON CORE | Summary: PMID:11971948 demonstrates that IL-4-deficient mice have a 100% incidence of gallstones and cholesterol crystals on a fat-enriched diet, compared to no gallstones in wild-type mice, suggesting IL-4 plays a role in cholesterol metabolism. ISS from mouse IL-4 (P07750). Reason: The paper provides genetic evidence that IL-4 deficiency predisposes to gallstone formation and altered cholesterol metabolism. However, this is a pleiotropic downstream effect rather than a core immune function of IL-4. Supporting Evidence: PMID:11971948 IL-4(-/-) mice had a 100% incidence of gallstones and cholesterol crystals |
| GO:0030890 positive regulation of B cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 promotes B cell proliferation as one of its defining functions. Originally named B-cell stimulatory factor 1 (BSF-1) for this activity. Transferred from mouse IL-4 (P07750). Reason: B cell proliferation is a core function of IL-4. It was originally identified as BSF-1 precisely for its B cell growth-promoting activity. The ISS from mouse is well-supported by extensive human data. Supporting Evidence: file:human/IL4/IL4-uniprot.txt AltName...B-cell stimulatory factor 1; Short=BSF-1 |
| GO:0042102 positive regulation of T cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 promotes T cell proliferation, particularly of Th2-committed cells. Also known as lymphocyte stimulatory factor 1. Transferred from mouse IL-4 (P07750). Reason: T cell proliferation promotion is a known function of IL-4, consistent with its alternative name as lymphocyte stimulatory factor 1. The ISS from mouse is well-supported. Supporting Evidence: file:human/IL4/IL4-uniprot.txt AltName...Lymphocyte stimulatory factor 1 |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has well-documented anti-apoptotic effects, promoting survival of B cells, T cells, and other immune cells through PI3K/Akt signaling. Transferred from mouse IL-4 (P07750). Reason: While IL-4 has anti-apoptotic effects through IRS-2/PI3K signaling, this is a secondary consequence of its signaling rather than a core function. The annotation is not incorrect but represents a downstream effect. |
| GO:0045348 positive regulation of MHC class II biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 induces MHC class II expression on B cells, enhancing their antigen-presenting capacity. This is one of IL-4's original defining functions. Transferred from mouse IL-4 (P07750). Reason: MHC class II upregulation on B cells by IL-4 is one of the earliest described functions of this cytokine and is directly documented in the UniProt function annotation. The ISS from mouse is well-supported by human data. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Induces the expression of class II MHC molecules on resting B-cells |
| GO:0045671 negative regulation of osteoclast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-4 has been reported to inhibit osteoclast differentiation, likely through anti-inflammatory effects that oppose RANKL signaling. Transferred from mouse IL-4 (P07750). Reason: While IL-4 may inhibit osteoclastogenesis, this is a specialized tissue-specific effect rather than a core immune function. The ISS annotation is from mouse data and represents a pleiotropic activity. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 activates RNA polymerase II-dependent transcription through STAT6-mediated signaling. Transferred from mouse IL-4 (P07750). Reason: This is well-supported by the IGI annotation with the same term from PMID:12574355 and by the known mechanism of STAT6-dependent gene activation. The ISS from mouse is consistent with human data. |
| GO:0048295 positive regulation of isotype switching to IgE isotypes | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 is the primary cytokine that drives B cell class switch recombination to IgE. This is arguably the most important and specific function of IL-4 in adaptive immunity, and the basis for anti-IL-4 therapy in allergic disease. Transferred from mouse IL-4 (P07750). Reason: IgE class switching is THE defining function of IL-4 in B cell biology. IL-4 induces germline epsilon transcription through STAT6 signaling, which is required for IgE class switch recombination. This is the mechanistic basis for dupilumab therapy in allergic diseases. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Enhances both secretion and cell surface expression of IgE and IgG1 file:human/IL4/IL4-deep-research-falcon.md IL-4 drives...B-cell proliferation and class-switch recombination to IgE |
| GO:0048304 positive regulation of isotype switching to IgG isotypes | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 promotes IgG1 (in mouse) and IgG4 (in human) class switching. Transferred from mouse IL-4 (P07750). Reason: IL-4 promotes IgG class switching in addition to IgE switching. In humans, IL-4 drives switching to IgG4; in mice, to IgG1. This is a well-established function. Supporting Evidence: file:human/IL4/IL4-uniprot.txt Enhances both secretion and cell surface expression of IgE and IgG1 |
| GO:0050776 regulation of immune response | ISS GO_REF:0000024 | ACCEPT | Summary: IL-4 regulates immune responses, particularly type 2 immunity. Transferred from mouse IL-4 (P07750). Duplicate of the IBA annotation. Reason: Duplicate of the IBA annotation with ISS evidence. Both are correct and complementary. |
| GO:0005136 interleukin-4 receptor binding | TAS PMID:3016727 Isolation and characterization of a human interleukin cDNA c... | ACCEPT | Summary: PMID:3016727 is the original paper by Yokota et al. (1986) reporting the cloning and characterization of human IL-4 cDNA, including its B-cell and T-cell stimulating activities through receptor binding. Reason: This is the seminal paper identifying human IL-4. The TAS annotation for IL-4 receptor binding from the original characterization paper is historically and scientifically well-supported. Supporting Evidence: PMID:3016727 Supernatant of COS-7 monkey cells transfected with the human cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated human B cells, two properties of mouse BSF-1 on mouse cells file:human/IL4/IL4-uniprot.txt NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION...Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1 |
| GO:0005615 extracellular space | TAS PMID:3016727 Isolation and characterization of a human interleukin cDNA c... | ACCEPT | Summary: The original IL-4 cloning paper by Yokota et al. (1986) characterizes IL-4 as a secreted protein with a putative signal peptide and extracellular activity. Reason: Correct localization annotation from the original characterization paper. Supporting Evidence: PMID:3016727 The human cDNA contains a single open reading frame encoding a protein of 153 amino acid residues including a putative signal peptide |
| GO:0006955 immune response | TAS PMID:3016727 Isolation and characterization of a human interleukin cDNA c... | ACCEPT | Summary: IL-4 was characterized as an immune response cytokine in the original cloning paper, showing B-cell and T-cell stimulating activities. Reason: IL-4 is fundamentally an immune response mediator. The TAS annotation from the original characterization paper is correct. Supporting Evidence: PMID:3016727 Supernatant of COS-7 monkey cells transfected with the human cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated human B cells |
| GO:0005136 interleukin-4 receptor binding | TAS PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... | ACCEPT | Summary: PMID:11418631 studies IL-4 receptor-mediated signaling in the context of germinal center B cell differentiation, demonstrating that IL-4 acts through its receptor to direct GC-B cell fate toward memory B cells. Reason: IL-4 receptor binding is the core molecular function. The paper demonstrates IL-4 receptor-mediated biological effects. Duplicate with different reference is acceptable. Supporting Evidence: PMID:11418631 IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC |
| GO:0005615 extracellular space | TAS PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... | ACCEPT | Summary: PMID:11418631 studies the effects of T cell-derived cytokines including secreted IL-4 on germinal center B cell differentiation, consistent with IL-4 activity in the extracellular space. Reason: Correct localization. IL-4 is a secreted cytokine that acts in the extracellular space. Duplicate with different reference is acceptable. Supporting Evidence: PMID:11418631 cytokines secreted by activated T cells determined the pathway of GC-B cell differentiation |
| GO:0008083 growth factor activity | NAS PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... | KEEP AS NON CORE | Summary: PMID:11418631 demonstrates that IL-4 and FDC signals provide growth-promoting signals for germinal center B cells. IL-4 has growth factor activity for B and T cells (originally named BSF-1). Reason: While IL-4 has growth-promoting activity for lymphocytes, its primary molecular function is better described as cytokine activity and IL-4 receptor binding. Growth factor activity is a secondary characterization. Supporting Evidence: PMID:11418631 FDC/HK cells do not direct either pathway, but provide signals for proliferation of GC-B cells |
| GO:0030183 B cell differentiation | TAS PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... | ACCEPT | Summary: PMID:11418631 directly demonstrates that IL-4 directs germinal center B cells to differentiate into memory B cells, while IL-10 steers them toward plasma cells. Reason: B cell differentiation is a core function of IL-4. The paper provides direct evidence for IL-4's role in directing GC-B cell differentiation pathways. Supporting Evidence: PMID:11418631 IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC file:human/IL4/IL4-uniprot.txt Enhances both secretion and cell surface expression of IgE and IgG1 |
| GO:0042092 type 2 immune response | TAS PMID:11676128 [Inflammatory cytokines (IL-4, IL-5 and IL-13)]. | ACCEPT | Summary: PMID:11676128 reviews IL-4, IL-5, and IL-13 as Th2 cytokines pivotal in regulating the allergic phenotype, IgE response, and inflammatory cell-mediated function. IL-4 is THE defining cytokine of type 2 immune responses. Reason: Type 2 immune response is the most accurate high-level description of IL-4's biological role. IL-4 is the master regulator of type 2 immunity. Supporting Evidence: PMID:11676128 Th2 cytokines, such as IL-4, IL-5 and IL-13, are pivotal in regulating the allergic phenotype, the IgE response or the inflammatory cell-mediated function file:human/IL4/IL4-deep-research-falcon.md IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic) across airway and barrier diseases |
| GO:0045191 regulation of isotype switching | TAS PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... | ACCEPT | Summary: PMID:11418631 studies the role of T cell-derived cytokines including IL-4 in germinal center B cell differentiation, which includes isotype switching. IL-4 is the primary cytokine regulating class switch recombination to IgE and IgG4 in humans. Reason: Isotype switching regulation is a core function of IL-4. More specific child terms (IgE and IgG switching) are also annotated. This general term appropriately captures the broader regulatory role. Supporting Evidence: PMID:11418631 IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC file:human/IL4/IL4-uniprot.txt Enhances both secretion and cell surface expression of IgE and IgG1 |
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