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Gene Review

Il4  -  interleukin 4

Mus musculus

Synonyms: B-cell IgG differentiation factor, B-cell growth factor 1, B-cell stimulatory factor 1, BSF-1, IGG1 induction factor, ...
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Disease relevance of Il4


Psychiatry related information on Il4

  • The treatment with the above agents had no effect on the total autoantibody titres; however, a decrease in the immunoglobulin G (IgG)2a/IgG1 ratio of the anti-DNA antibodies was determined in the 16/6 Id immunized and treated mice [6].
  • Our results indicated that IL-4 suppressed the host defense mechanisms against infection with C. neoformans potentiated by IFN-gamma-inducing cytokines probably through the suppression of local production of IFN-gamma [7].
  • Intergenic transcription is not required in Th2 cells to maintain histone acetylation and transcriptional permissiveness at the Il4-Il13 locus [8].
  • Time-response profiles of epidermal IL1beta, TNFalpha, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions [9].
  • Our previous work has documented that physical or psychological stress can alter interleukin (IL)-2, IL-4, and interferon (IFN)-gamma production by spleen or lymph node cells in vitro [10].

High impact information on Il4

  • 6. A late-acting form of T-cell help other than IL-4 appears to be required for the generation of an IgE, but not an IgG1 response [11].
  • Memory B cells that have already switched to IgE at the DNA level may no longer require stimulation with IL-4 to be induced to secrete IgE [11].
  • IL-4 acts as a myoblast recruitment factor during mammalian muscle growth [12].
  • Muscle cells lacking IL-4 or the IL-4alpha receptor subunit form normally but are reduced in size and myonuclear number [12].
  • These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth [12].

Genetic context of IL-4




Chemical compound and disease context of Il4


Biological context of Il4


Anatomical context of Il4


Associations of Il4 with chemical compounds

  • We show here that ligation of surface immunoglobulin or CD40 receptors in conjunction with interleukin-4 induces the nuclear factor of activated T cells (NF-AT) in normal murine B cells, which is inhibited by cyclosporin (CsA) [32].
  • Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation [33].
  • In this paper, we show that the survival of resting T cells in vitro is promoted by two cytokines, interleukins 4 and 7 (IL-4, IL-7) [34].
  • The effector T cells provided excellent helper activity for in vitro antibody responses of 4-hydroxy-5-iodo-nitrophenyl acetic acid-primed B cells with the production principally of the immunoglobulin G1 (IgG1) and IgM isotypes, small quantities of IgG3, and no detectable IgG2a, or IgG2b [35].
  • These data demonstrate a marked difference in the IL-4 dependence of Th2 responses generated at two anatomic sites of natural allergen encounter and identify the skin as a particularly potent site for Th2 sensitization [36].
  • They also demonstrate that IL-4 has different effects on adenosine metabolism in Balb/c and C57BL/6 mice and that these differences contribute to the different responses that IL-4 induces in these inbred animals [37].

Physical interactions of Il4


Enzymatic interactions of Il4

  • Furthermore, IL-4 phosphorylated the 65-kd isoform of Stat6 in BMMCs from wild-type mice but not from gamma(c)(-) and Jak3(-) mice [43].
  • c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway [44].
  • IL-4 treatment of FDCP-2 cells caused a dramatically strong association of phosphatidylinositol 3-kinase (PI 3-kinase) both with the 170 kDa tyrosine phosphorylated substrate and with the IL-4 receptor itself [45].

Regulatory relationships of Il4


Other interactions of Il4

  • Previous studies have shown that murine BSF-1 can be separated physically from interleukin-2 (IL-2) and that the molecule has an apparent relative molecular mass (Mr) of approximately 15,000 and pI values of 6.4-6.7 and 7 [26].
  • Based on these probabilities, individual cells randomly express Il4 and Il13 alleles [27].
  • Stat6 is required for mediating responses to IL-4 and for development of Th2 cells [31].
  • Purified IL-4 producers and nonproducers have similar Gata3 and c-maf mRNA expression [1].
  • Dnmt1-/- CD4 and CD8 T cells derepress IL-4 expression considerably, demethylate DNA and increase H3 Lys4 methylation without affecting GATA-3 expression, demonstrating that Dnmt1 and DNA methylation are essential for proper Il4 regulation [23].

Analytical, diagnostic and therapeutic context of Il4

  • In the liver of NOD mice, we detected mouse Il4 and Il10 mRNA 5 days after intravenous injection of both PAGA-Il4 and PAGA-Il10 plasmid complexes [2].
  • To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting [5].
  • A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo [52].
  • CD4+ T cells of IL-4-deficient mice showed impaired Th2 cell development, as assessed by quantitative RT-PCR of characteristic cytokines [53].
  • IL-2, IL-4, and tumor necrosis factor beta (IFN beta) comprised the third group and these cytokines were expressed only in allogeneic grafts after transplantation [54].


  1. Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus. Guo, L., Hu-Li, J., Paul, W.E. Immunity (2004) [Pubmed]
  2. Combined administration of plasmids encoding IL-4 and IL-10 prevents the development of autoimmune diabetes in nonobese diabetic mice. Ko, K.S., Lee, M., Koh, J.J., Kim, S.W. Mol. Ther. (2001) [Pubmed]
  3. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Kopf, M., Le Gros, G., Bachmann, M., Lamers, M.C., Bluethmann, H., Köhler, G. Nature (1993) [Pubmed]
  4. Differential production of interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by gamma delta T cells in vivo. Ferrick, D.A., Schrenzel, M.D., Mulvania, T., Hsieh, B., Ferlin, W.G., Lepper, H. Nature (1995) [Pubmed]
  5. Essential role of Stat6 in IL-4 signalling. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., Akira, S. Nature (1996) [Pubmed]
  6. The beneficial effects of treatment with tamoxifen and anti-oestradiol antibody on experimental systemic lupus erythematosus are associated with cytokine modulations. Dayan, M., Zinger, H., Kalush, F., Mor, G., Amir-Zaltzman, Y., Kohen, F., Sthoeger, Z., Mozes, E. Immunology (1997) [Pubmed]
  7. Interleukin-4 weakens host resistance to pulmonary and disseminated cryptococcal infection caused by combined treatment with interferon-gamma-inducing cytokines. Kawakami, K., Hossain Qureshi, M., Zhang, T., Koguchi, Y., Xie, Q., Kurimoto, M., Saito, A. Cell. Immunol. (1999) [Pubmed]
  8. Intergenic transcription is not required in Th2 cells to maintain histone acetylation and transcriptional permissiveness at the Il4-Il13 locus. Baguet, A., Sun, X., Arroll, T., Krumm, A., Bix, M. J. Immunol. (2005) [Pubmed]
  9. Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a direct correlation between carcinogen-induced contact hypersensitivity and epidermal hyperplasia. Casale, G.P., Cheng, Z., Liu, J., Cavalieri, E.L., Singhal, M. Mol. Carcinog. (2000) [Pubmed]
  10. Adrenal hormone modulation of type 1 and type 2 cytokine production by spleen cells: dexamethasone and dehydroepiandrosterone suppress interleukin-2, interleukin-4, and interferon-gamma production in vitro. Moynihan, J.A., Callahan, T.A., Kelley, S.P., Campbell, L.M. Cell. Immunol. (1998) [Pubmed]
  11. Lymphokine control of in vivo immunoglobulin isotype selection. Finkelman, F.D., Holmes, J., Katona, I.M., Urban, J.F., Beckmann, M.P., Park, L.S., Schooley, K.A., Coffman, R.L., Mosmann, T.R., Paul, W.E. Annu. Rev. Immunol. (1990) [Pubmed]
  12. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Horsley, V., Jansen, K.M., Mills, S.T., Pavlath, G.K. Cell (2003) [Pubmed]
  13. The production of two Th2 cytokines, interleukin-4 and interleukin-10, is controlled independently by locus Cypr1 and by loci Cypr2 and Cypr3, respectively. Kosarová, M., Havelková, H., Krulová, M., Demant, P., Lipoldová, M. Immunogenetics. (1999) [Pubmed]
  14. Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes. Lipoldová, M., Svobodová, M., Krulová, M., Havelková, H., Badalová, J., Nohýnková, E., Holán, V., Hart, A.A., Volf, P., Demant, P. Genes. Immun. (2000) [Pubmed]
  15. Distinct genetic control of parasite elimination, dissemination, and disease after Leishmania major infection. Kurey, I., Kobets, T., Havelková, H., Slapničková, M., Quan, L., Trtková, K., Grekov, I., Svobodová, M., Stassen, A.P., Hutson, A., Demant, P., Lipoldová, M. Immunogenetics. (2009) [Pubmed]
  16. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects. Havelková, H., Badalová, J., Svobodová, M., Vojtíková, J., Kurey, I., Vladimirov, V., Demant, P., Lipoldová, M. Genes. Immun. (2006) [Pubmed]
  17. Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility. Lipoldová, M., Havelková, H., Badalová, J., Demant, P. Int. J. Cancer. (2005) [Pubmed]
  18. Immunity to Trichinella spiralis infection in vitamin A-deficient mice. Carman, J.A., Pond, L., Nashold, F., Wassom, D.L., Hayes, C.E. J. Exp. Med. (1992) [Pubmed]
  19. Development of murine allergic asthma is dependent upon B7-2 costimulation. Keane-Myers, A.M., Gause, W.C., Finkelman, F.D., Xhou, X.D., Wills-Karp, M. J. Immunol. (1998) [Pubmed]
  20. Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter. Chuvpilo, S., Schomberg, C., Gerwig, R., Heinfling, A., Reeves, R., Grummt, F., Serfling, E. Nucleic Acids Res. (1993) [Pubmed]
  21. Role of interleukin-4 (IL-4) and IL-10 in serum immunoglobulin G antibody responses following mucosal or systemic reovirus infection. Mathers, A.R., Cuff, C.F. J. Virol. (2004) [Pubmed]
  22. Impaired contact hypersensitivity to trinitrochlorobenzene in interleukin-4-deficient mice. Dieli, F., Sireci, G., Scirè, E., Salerno, A., Bellavia, A. Immunology (1999) [Pubmed]
  23. Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Makar, K.W., Pérez-Melgosa, M., Shnyreva, M., Weaver, W.M., Fitzpatrick, D.R., Wilson, C.B. Nat. Immunol. (2003) [Pubmed]
  24. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. Koyanagi, M., Baguet, A., Martens, J., Margueron, R., Jenuwein, T., Bix, M. J. Biol. Chem. (2005) [Pubmed]
  25. Identification of 40 genes on a 1-Mb contig around the IL-4 cytokine family gene cluster on mouse chromosome 11. Wenderfer, S.E., Slack, J.P., McCluskey, T.S., Monaco, J.J. Genomics (2000) [Pubmed]
  26. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Ohara, J., Paul, W.E. Nature (1985) [Pubmed]
  27. Probabilistic regulation in TH2 cells accounts for monoallelic expression of IL-4 and IL-13. Guo, L., Hu-Li, J., Paul, W.E. Immunity (2005) [Pubmed]
  28. Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity. Ansel, K.M., Greenwald, R.J., Agarwal, S., Bassing, C.H., Monticelli, S., Interlandi, J., Djuretic, I.M., Lee, D.U., Sharpe, A.H., Alt, F.W., Rao, A. Nat. Immunol. (2004) [Pubmed]
  29. B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells. Brown, M.A., Pierce, J.H., Watson, C.J., Falco, J., Ihle, J.N., Paul, W.E. Cell (1987) [Pubmed]
  30. Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Kinashi, T., Harada, N., Severinson, E., Tanabe, T., Sideras, P., Konishi, M., Azuma, C., Tominaga, A., Bergstedt-Lindqvist, S., Takahashi, M. Nature (1986) [Pubmed]
  31. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Kaplan, M.H., Schindler, U., Smiley, S.T., Grusby, M.J. Immunity (1996) [Pubmed]
  32. Induction of NF-AT in normal B lymphocytes by anti-immunoglobulin or CD40 ligand in conjunction with IL-4. Choi, M.S., Brines, R.D., Holman, M.J., Klaus, G.G. Immunity (1994) [Pubmed]
  33. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. Stein, M., Keshav, S., Harris, N., Gordon, S. J. Exp. Med. (1992) [Pubmed]
  34. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. Vella, A., Teague, T.K., Ihle, J., Kappler, J., Marrack, P. J. Exp. Med. (1997) [Pubmed]
  35. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. Bradley, L.M., Duncan, D.D., Tonkonogy, S., Swain, S.L. J. Exp. Med. (1991) [Pubmed]
  36. Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4. Herrick, C.A., MacLeod, H., Glusac, E., Tigelaar, R.E., Bottomly, K. J. Clin. Invest. (2000) [Pubmed]
  37. Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis. Ma, B., Blackburn, M.R., Lee, C.G., Homer, R.J., Liu, W., Flavell, R.A., Boyden, L., Lifton, R.P., Sun, C.X., Young, H.W., Elias, J.A. J. Clin. Invest. (2006) [Pubmed]
  38. Interleukin-6 interacts with interleukin-4 and other hematopoietic growth factors to selectively enhance the growth of megakaryocytic, erythroid, myeloid, and multipotential progenitor cells. Rennick, D., Jackson, J., Yang, G., Wideman, J., Lee, F., Hudak, S. Blood (1989) [Pubmed]
  39. JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes. Yin, T., Tsang, M.L., Yang, Y.C. J. Biol. Chem. (1994) [Pubmed]
  40. Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins. Gold, M.R., Duronio, V., Saxena, S.P., Schrader, J.W., Aebersold, R. J. Biol. Chem. (1994) [Pubmed]
  41. CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite. Lu, P., Zhou, X., Chen, S.J., Moorman, M., Morris, S.C., Finkelman, F.D., Linsley, P., Urban, J.F., Gause, W.C. J. Exp. Med. (1994) [Pubmed]
  42. Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer. Naoe, Y., Setoguchi, R., Akiyama, K., Muroi, S., Kuroda, M., Hatam, F., Littman, D.R., Taniuchi, I. J. Exp. Med. (2007) [Pubmed]
  43. Role of common cytokine receptor gamma chain (gamma(c))- and Jak3-dependent signaling in the proliferation and survival of murine mast cells. Suzuki, K., Nakajima, H., Watanabe, N., Kagami, S., Suto, A., Saito, Y., Saito, T., Iwamoto, I. Blood (2000) [Pubmed]
  44. c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway. Ueno, H., Sasaki, K., Honda, H., Nakamoto, T., Yamagata, T., Miyagawa, K., Mitani, K., Yazaki, Y., Hirai, H. Blood (1998) [Pubmed]
  45. IL-4 activates a distinct signal transduction cascade from IL-3 in factor-dependent myeloid cells. Wang, L.M., Keegan, A.D., Paul, W.E., Heidaran, M.A., Gutkind, J.S., Pierce, J.H. EMBO J. (1992) [Pubmed]
  46. Interleukin 5 induces S mu-S gamma 1 DNA rearrangement in B cells activated with dextran-anti-IgD antibodies and interleukin 4: a three component model for Ig class switching. Mandler, R., Chu, C.C., Paul, W.E., Max, E.E., Snapper, C.M. J. Exp. Med. (1993) [Pubmed]
  47. Interleukin 13: novel role in direct regulation of proliferation and differentiation of primitive hematopoietic progenitor cells. Jacobsen, S.E., Okkenhaug, C., Veiby, O.P., Caput, D., Ferrara, P., Minty, A. J. Exp. Med. (1994) [Pubmed]
  48. IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. Suzuki, K., Nakajima, H., Ikeda, K., Maezawa, Y., Suto, A., Takatori, H., Saito, Y., Iwamoto, I. J. Exp. Med. (2003) [Pubmed]
  49. Interleukin 2 plays a central role in Th2 differentiation. Cote-Sierra, J., Foucras, G., Guo, L., Chiodetti, L., Young, H.A., Hu-Li, J., Zhu, J., Paul, W.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  50. Interleukin 4 (B-cell stimulatory factor 1) can enhance or antagonize the factor-dependent growth of hemopoietic progenitor cells. Rennick, D., Yang, G., Muller-Sieburg, C., Smith, C., Arai, N., Takabe, Y., Gemmell, L. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  51. Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. Dufort, F.J., Bleiman, B.F., Gumina, M.R., Blair, D., Wagner, D.J., Roberts, M.F., Abu-Amer, Y., Chiles, T.C. J. Immunol. (2007) [Pubmed]
  52. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Hodge, M.R., Ranger, A.M., Charles de la Brousse, F., Hoey, T., Grusby, M.J., Glimcher, L.H. Immunity (1996) [Pubmed]
  53. IL-4-deficient Balb/c mice resist infection with Leishmania major. Kopf, M., Brombacher, F., Köhler, G., Kienzle, G., Widmann, K.H., Lefrang, K., Humborg, C., Ledermann, B., Solbach, W. J. Exp. Med. (1996) [Pubmed]
  54. Cytokine gene transcription in vascularised organ grafts: analysis using semiquantitative polymerase chain reaction. Dallman, M.J., Larsen, C.P., Morris, P.J. J. Exp. Med. (1991) [Pubmed]
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