Genomes and Genes
Gene Symbol: Il4
Description: interleukin 4
Alias: BSF-1, Il-4, interleukin-4, B-cell IgG differentiation factor, B-cell growth factor 1, B-cell stimulatory factor 1, IGG1 induction factor, lymphocyte stimulatory factor 1
- Kiyota T, Okuyama S, Swan R, Jacobsen M, Gendelman H, Ikezu T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 2010;24:3093-102 pubmed publisher..Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD. ..
- Tang H, Cao W, Kasturi S, Ravindran R, Nakaya H, Kundu K, et al. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol. 2010;11:608-17 pubmed publisher..responses occur via 'cooperation' between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4)...
- Dickgreber N, Farrand K, van Panhuys N, Knight D, McKee S, Chong M, et al. Immature murine NKT cells pass through a stage of developmentally programmed innate IL-4 secretion. J Leukoc Biol. 2012;92:999-1009 pubmed publisher..These observations indicate a regulated pattern of IL-4 expression by maturing NKT cells, which may endow these cells with a capacity to influence the development of surrounding cells in the thymus. ..
- Sokol C, Chu N, Yu S, Nish S, Laufer T, Medzhitov R. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol. 2009;10:713-20 pubmed publisher..Thus, basophils function as antigen-presenting cells for T(H)2 differentiation in response to protease allergens...
- Morris S, Heidorn S, Herbert D, Perkins C, Hildeman D, Khodoun M, et al. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J Immunol. 2009;182:1429-38 pubmed..Thus, endogenously produced IL-4 is an important regulator of quantitative as well as qualitative aspects of T cell immunity. ..
- Szanto A, Balint B, Nagy Z, Barta E, Dezso B, Pap A, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPAR?-regulated gene expression in macrophages and dendritic cells. Immunity. 2010;33:699-712 pubmed publisher..This interaction, underpinning cell type-specific responses, represents a unique way of controlling nuclear receptor signaling by inflammatory molecules in immune cells. ..
- Hübner M, Shi Y, Torrero M, Mueller E, Larson D, Soloviova K, et al. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-?. J Immunol. 2012;188:559-68 pubmed publisher..This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-?. ..
- Dolgachev V, Petersen B, Budelsky A, Berlin A, Lukacs N. Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J Immunol. 2009;183:5705-15 pubmed publisher..Overall, these studies suggest a complex relationship between SCF, bone marrow-derived IL-25-responsive myeloid cells, Th2 cytokines, and chronic allergic disease. ..
- Charles N, Watford W, Ramos H, Hellman L, Oettgen H, Gomez G, et al. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity. 2009;30:533-43 pubmed publisher..Our findings demonstrate that basophil-expressed Lyn kinase exerts regulatory control on Th2 cell differentiation and function. ..
- Everts B, Hussaarts L, Driessen N, Meevissen M, Schramm G, van der Ham A, et al. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. J Exp Med. 2012;209:1753-67, S1 pubmed..These experiments reveal an unrecognized pathway involving MR and interference with protein synthesis that conditions DCs for Th2 priming...
- Veldhoen M, Uyttenhove C, Van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9:1341-6 pubmed publisher..Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways. ..
- Liang H, Reinhardt R, Bando J, Sullivan B, Ho I, Locksley R. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol. 2011;13:58-66 pubmed publisherb>Interleukin 4 (IL-4) and IL-13 are critical for responses to parasitic helminthes. We used genetically engineered reporter mice to assess the temporal and spatial production of these cytokines in vivo...
- Yusuf I, Kageyama R, Monticelli L, Johnston R, DiToro D, Hansen K, et al. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010;185:190-202 pubmed publisher..These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in T(FH) cell and GC T(FH) cell differentiation...
- RÃ¼ckerl D, Jenkins S, Laqtom N, Gallagher I, Sutherland T, Duncan S, et al. Induction of IL-4RÎ±-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo. Blood. 2012;120:2307-16 pubmed publisher..Together, the data suggest that negative regulation of Akt signaling via microRNAs might play a central role in limiting MÎ¦ expansion and alternative activation during type 2 inflammatory settings. ..
- King I, Mohrs M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med. 2009;206:1001-7 pubmed publisher..Our report reveals the compartmentalization of Th2 priming and IL-4 production in the lymph nodes during infection, and identifies Tfh cells as the dominant source of IL-4 in vivo. ..
- Yagi R, Junttila I, Wei G, Urban J, Zhao K, Paul W, et al. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma. Immunity. 2010;32:507-17 pubmed publisher..Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-gamma production in a STAT4- and T-bet-independent manner. ..
- Sasaki K, Zhao X, Pardee A, Ueda R, Fujita M, Sehra S, et al. Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo. J Immunol. 2008;181:104-8 pubmed..These results suggest that Stat6-signaling is necessary and sufficient to restrict CD8+ T cell expression of VLA-4 (by IL-4), thereby serving as a regulator for CD8+ T cell infiltration into tumors. ..
- Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel R, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008;9:1347-55 pubmed publisher..Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation. ..
- Hammad H, Plantinga M, Deswarte K, Pouliot P, Willart M, Kool M, et al. Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med. 2010;207:2097-111 pubmed publisher..Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen...
- Dittrich A, Chen H, Xu L, Ranney P, Connolly S, Yarovinsky T, et al. A new mechanism for inhalational priming: IL-4 bypasses innate immune signals. J Immunol. 2008;181:7307-15 pubmed..Our findings bring new mechanistic knowledge to the phenomenon of polysensitization and primary sensitization in asthma. ..
- Tozawa H, Kanki Y, Suehiro J, Tsutsumi S, Kohro T, Wada Y, et al. Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter. Mol Cell Biol. 2011;31:2196-209 pubmed publisher..Identification of a novel IL-4-mediated VCAM-1 enhancer may provide a foundation for targeted therapy in vascular disease. ..
- Cho J, Song D, Pham A, Rosenthal P, Miller M, Dayan S, et al. Chronic OVA allergen challenged Siglec-F deficient mice have increased mucus, remodeling, and epithelial Siglec-F ligands which are up-regulated by IL-4 and IL-13. Respir Res. 2010;11:154 pubmed publisher..In addition, IL-4 and IL-13 are important regulators of Siglec-F ligand expression by airway epithelium. ..
- Gao Y, Nish S, Jiang R, Hou L, Licona Limón P, Weinstein J, et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity. 2013;39:722-32 pubmed publisher..IRF4 is known to control Th2 cell differentiation and Th2 cell-associated suppressing function in Treg cells. Our finding suggests that IRF4 also plays a role in DCs where it controls the initiation of Th2 cell responses...
- Fukuyama T, Kasper L, Boussouar F, Jeevan T, van Deursen J, Brindle P. Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development. Mol Cell Biol. 2009;29:3894-904 pubmed publisher..CBP therefore defines a nuclear component of the signaling pathways that demarcate the development of innate and adaptive naïve CD8(+) T cells in the thymus. ..
- Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam K, et al. Activation of natural killer T cells promotes M2 Macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem. 2012;287:13561-71 pubmed publisher..Thus, our data identify a novel therapeutic target for the treatment of obesity-associated inflammation and type 2 diabetes. ..
- Tanaka S, Motomura Y, Suzuki Y, Yagi R, Inoue H, Miyatake S, et al. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol. 2011;12:77-85 pubmed publisher..Here we identify the DNase I-hypersensitive site 2 (HS2) element located in the second intron of the interleukin 4 locus (Il4) as a critical enhancer strictly controlled by GATA-3 binding...
- Apte S, Baz A, Groves P, Kelso A, Kienzle N. Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells. Proc Natl Acad Sci U S A. 2008;105:17475-80 pubmed publisher..The data reveal an unexpected role for IFN-gamma in tuning the CD8 co-receptor during primary CD8(+) T cell activation both in vitro and in vivo. ..
- Varin A, Mukhopadhyay S, Herbein G, Gordon S. Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion. Blood. 2010;115:353-62 pubmed publisher..These findings are relevant to host defense in mixed infections within a Th2 microenvironment and shed light on immunologic functions associated with alternative priming and full activation of macrophages...
- Sullivan B, Liang H, Bando J, WU D, Cheng L, McKerrow J, et al. Genetic analysis of basophil function in vivo. Nat Immunol. 2011;12:527-35 pubmed publisherContributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive interleukin 4 (Il4) reporter alleles, we demonstrate here that basophil IL-4 production occurs by a CD4(+) T cell-dependent process ..
- Reinhardt R, Liang H, Locksley R. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol. 2009;10:385-93 pubmed publisher..Using an interleukin 4-reporter system, we show here that CD4(+) follicular helper T cells constituted essentially all of the ..
- WU D, Molofsky A, Liang H, Ricardo Gonzalez R, Jouihan H, Bando J, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332:243-7 pubmed publisher..Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs. ..
- Egawa M, Mukai K, Yoshikawa S, Iki M, Mukaida N, Kawano Y, et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity. 2013;38:570-80 pubmed publisher..Thus, inflammatory monocytes can be converted from being proinflammatory to anti-inflammatory under the influence of basophils in allergic reactions...
- Price A, Liang H, Sullivan B, Reinhardt R, Eisley C, Erle D, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010;107:11489-94 pubmed publisher..Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses. ..
- Elliott D, Metwali A, Leung J, Setiawan T, Blum A, Ince M, et al. Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production. J Immunol. 2008;181:2414-9 pubmed..Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation...
- Oliver J, Stolberg V, Chensue S, King P. IL-4 acts as a potent stimulator of IFN-? expression in CD8+ T cells through STAT6-dependent and independent induction of Eomesodermin and T-bet. Cytokine. 2012;57:191-9 pubmed publisher..These novel findings point to a function for IL-4 as a direct regulator of IFN-? expression in CD8+ T cells and reveal the molecular mechanisms involved. ..
- Nguyen K, Qiu Y, Cui X, Goh Y, Mwangi J, David T, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480:104-8 pubmed publisher..Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. ..
- Perona Wright G, Mohrs K, Taylor J, Zaph C, Artis D, Pearce E, et al. Cutting edge: Helminth infection induces IgE in the absence of mu- or delta-chain expression. J Immunol. 2008;181:6697-701 pubmed..Our findings reveal the existence of an evolutionarily conserved, IgM-independent pathway for the production of IgE upon infection with helminth parasites. ..
- Denzel A, Maus U, Rodriguez Gomez M, Moll C, Niedermeier M, Winter C, et al. Basophils enhance immunological memory responses. Nat Immunol. 2008;9:733-42 pubmed publisher..These basophil-dependent effects on B cells required interleukins 6 and 4 and increased the capacity of CD4(+) T cells to provide B cell help. Thus, basophils are important contributors to humoral memory immune responses. ..
- Kroeger K, Sullivan B, Locksley R. IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol. 2009;86:769-78 pubmed publisher..In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils. ..
- Kurowska Stolarska M, Kewin P, Murphy G, Russo R, Stolarski B, Garcia C, et al. IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol. 2008;181:4780-90 pubmed..Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4...
- Mukherjee S, Chen L, Papadimos T, Huang S, Zuraw B, Pan Z. Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. J Biol Chem. 2009;284:29391-8 pubmed publisher..These findings suggest a novel function of LPS and the signaling pathways in the induction of IL-4 gene expression. ..
- Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A. 2010;107:18581-6 pubmed publisher..These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses. ..
- Verykokakis M, Boos M, Bendelac A, Kee B. SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity. 2010;33:203-15 pubmed publisher..Our findings reveal that accumulation of NKT-like cells promotes conventional CD8(+) thymocytes to acquire innate lymphocyte characteristics. ..
- Heredia J, Mukundan L, Chen F, Mueller A, Deo R, Locksley R, et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell. 2013;153:376-88 pubmed publisher..Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues. ..
- Neill D, Wong S, Bellosi A, Flynn R, Daly M, Langford T, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464:1367-70 pubmed publisher..Thus, nuocytes represent a critically important innate effector cell in type-2 immunity...
- Zhou Y, Sonobe Y, Akahori T, Jin S, Kawanokuchi J, Noda M, et al. IL-9 promotes Th17 cell migration into the central nervous system via CC chemokine ligand-20 produced by astrocytes. J Immunol. 2011;186:4415-21 pubmed publisher..These results suggest that IL-9 is produced by several Th cell subsets in the presence of IL-4 and induces CCL-20 production by astrocytes to induce the migration of Th17 cells into the CNS. ..
- Fallon P, Ballantyne S, Mangan N, Barlow J, Dasvarma A, Hewett D, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med. 2006;203:1105-16 pubmed..We demonstrate that these IL-25-regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion...
- Chen L, Grabowski K, Xin J, Coleman J, Huang Z, Espiritu B, et al. IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils. J Immunol. 2004;172:2059-66 pubmed..These results strongly suggest IL-4 is a potent factor in directing bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils. ..