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Gene Review

IL4  -  interleukin 4

Homo sapiens

Synonyms: B-cell stimulatory factor 1, BCGF-1, BCGF1, BSF-1, BSF1, ...
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Disease relevance of IL4


Psychiatry related information on IL4


High impact information on IL4

  • Pavlath and coworkers demonstrate a novel role for Interleukin-4 (IL-4) in regulating the fusion of myoblasts with differentiated myotubes [10].
  • The authors demonstrate that NFATc2 signaling in newly formed myotubes induces IL-4 expression and secretion which promotes myoblast fusion with pre-existing myotubes [10].
  • IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP) [11].
  • Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression [12].
  • The R576 allele was associated with higher levels of expression of CD23 by interleukin-4 than the wild-type allele [13].

Chemical compound and disease context of IL4


Biological context of IL4


Anatomical context of IL4

  • However, while IL2 expression requires the contribution of Ca(2+)- and protein kinase C-dependent signals, we report that activation of human IL4 transcription through the Ca(2+)-dependent pathway is diminished by protein kinase C stimulation in Jurkat T cells [19].
  • In normal human peripheral blood lymphocytes (PBL), IL4 does not induce LAK activity and inhibits LAK induction by IL2 [24].
  • In human B cells, interleukin 4 (IL4) acts in regulating proliferation, antigen expression, isotype switching and differentiation [25].
  • These results show that the induction of IgE synthesis by recombinant IL4 is T cell dependent and optimal in the presence of monocytes [26].
  • CONCLUSION: In the presence of TGF beta 1 or IL4, fibroblasts derived from synovial tissue or synovial fluid are induced to differentiate into myofibroblast-like cells containing the alpha smooth muscle form of actin [27].

Associations of IL4 with chemical compounds

  • Alanine substitutions of these conserved residues revealed that the transactivation domain, which localized Ser(756) but not Ser(827) or Ser(176), is the IL4-regulated site based on phosphoamino acid analysis [22].
  • In addition, the in vitro effect of dexamethasone (0.02, 0.2, and 2 microM) on PB MNC IL10, IFN gamma, and IL4 production was studied [28].
  • Prostaglandin E2 potently enhanced IgE production stimulated with IL4 alone but was inhibitory in the presence of anti-CD40 as a co-stimulatory signal [29].
  • Differences in IL4 signalling are likely due to crosstalk between integrin and cytokine signalling pathways, and not differences in IL4R expression [30].
  • Some authors have reported down-regulation of bcl-2 protein expression in B-CLL B-cells undergoing SA or in steroid-treated cells with IL4 preventing this down-regulation [31].
  • Removal of cell surface chondroitin sulfates by chondroitinase ABC strongly impaired IL-4-induced STAT6 phosphorylation, whereas removal of HS by heparinase III had only a weak inhibitory effect [32].

Physical interactions of IL4

  • IL-13 Induced the same complexes as IL-4, a finding explained by our studies implicating IL-4R as a shared component of the receptors [33].
  • However, cotransfection of all three chains did not further increase IL-4 binding or alter the extent of STAT6 activation suggesting that all three chains together do not seem to participate in IL-4 function [34].
  • In addition, IL-4-treated but not untreated mast cells bound to immobilized ICAM-1 [35].
  • Binding of IL-4 to the IL-13Ralpha(1)/IL-4Ralpha receptor complex leads to STAT3 phosphorylation but not to its nuclear translocation [36].
  • The IRF-1 allele 1 tended to interact with the IL-4 promoter -589 T genotype in the development of SSPE (P =.06), as judged on logistic regression analysis [37].

Enzymatic interactions of IL4

  • IL-4 receptor p140 protein was also constitutively phosphorylated in two of three EBV B cell lines examined and both IL-4 and IL-13 further augmented its phosphorylation [38].
  • In this study, we show that insulin receptor substrate (IRS)-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6) are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells [39].
  • Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4 [40].
  • Recently, we determined the solution structure of the phosphotyrosine binding (PTB) domain of the insulin receptor substrate (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the interleukin 4 (IL-4) receptor [Zhou et al., (1996) Nat. Struct. Biol. 3, 388-393] [41].
  • Interleukin-4/13 and transforming growth factor-beta-activated cells were identified by specific antibodies to phosphorylated (phospho-) signal transducer and activator of transcription 6 and phospho-Smad2, respectively [42].

Co-localisations of IL4

  • In cultured FRC, TG is induced 5- to 20-fold and becomes colocalized with matrix proteins by treatment with interleukin-4, but not by other cytokines that are commonly increased in lymph upon immune activation [43].

Regulatory relationships of IL4

  • Furthermore, when both lymphokines were added together at culture initiation, BSF-1 inhibited the IL-2-driven generation of cytolytic cells [44].
  • IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus [45].
  • Interleukin 8 (IL-8) selectively inhibits immunoglobulin E production induced by IL-4 in human B cells [46].
  • IL-13-induced IgG4 and IgE synthesis is IL-4-independent, since it was not affected by neutralizing anti-IL-4 monoclonal antibody [47].
  • In addition, we have examined the ability of 32D cells transfected with different truncation mutants of the human IL-4 receptor to activate Jak-3 kinase and STF-IL4 in response to human IL-4 [48].

Other interactions of IL4


Analytical, diagnostic and therapeutic context of IL4


  1. A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes. Puri, R.K., Mehrotra, P.T., Leland, P., Kreitman, R.J., Siegel, J.P., Pastan, I. J. Immunol. (1994) [Pubmed]
  2. A wide range of human cancers express interleukin 4 (IL4) receptors that can be targeted with chimeric toxin composed of IL4 and Pseudomonas exotoxin. Debinski, W., Puri, R.K., Kreitman, R.J., Pastan, I. J. Biol. Chem. (1993) [Pubmed]
  3. Receptor for interleukin (IL) 13 does not interact with IL4 but receptor for IL4 interacts with IL13 on human glioma cells. Debinski, W., Miner, R., Leland, P., Obiri, N.I., Puri, R.K. J. Biol. Chem. (1996) [Pubmed]
  4. A common haplotype of interleukin-4 gene IL4 is associated with severe respiratory syncytial virus disease in Korean children. Choi, E.H., Lee, H.J., Yoo, T., Chanock, S.J. J. Infect. Dis. (2002) [Pubmed]
  5. Cytokine and chemokine gene polymorphisms among ethnically diverse North Americans with HIV-1 infection. Wang, C., Song, W., Lobashevsky, E., Wilson, C.M., Douglas, S.D., Mytilineos, J., Schoenbaum, E.E., Tang, J., Kaslow, R.A. J. Acquir. Immune Defic. Syndr. (2004) [Pubmed]
  6. Correlation between serum levels of interleukin-4 and alexithymia scores in healthy female subjects: preliminary findings. Corcos, M., Guilbaud, O., Paterniti, S., Curt, F., Hjalmarsson, L., Moussa, M., Chambry, J., Loas, G., Chaouat, G., Jeammet, P. Psychoneuroendocrinology (2004) [Pubmed]
  7. Reduced alloreactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFNgamma levels. Szabo, G., Mandrekar, P., Dolganiuc, A., Catalano, D., Kodys, K. Alcohol. Clin. Exp. Res. (2001) [Pubmed]
  8. Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Dimitrov, S., Lange, T., Tieken, S., Fehm, H.L., Born, J. Brain Behav. Immun. (2004) [Pubmed]
  9. Interleukin 4 and interleukin 10 levels are elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Stoeck, K., Bodemer, M., Ciesielczyk, B., Meissner, B., Bartl, M., Heinemann, U., Zerr, I. Arch. Neurol. (2005) [Pubmed]
  10. Fusion with the fused: a new role for interleukin-4 in the building of muscle. Chargé, S., Rudnicki, M.A. Cell (2003) [Pubmed]
  11. Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Hage, T., Sebald, W., Reinemer, P. Cell (1999) [Pubmed]
  12. Long-term clinical efficacy of grass-pollen immunotherapy. Durham, S.R., Walker, S.M., Varga, E.M., Jacobson, M.R., O'Brien, F., Noble, W., Till, S.J., Hamid, Q.A., Nouri-Aria, K.T. N. Engl. J. Med. (1999) [Pubmed]
  13. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. Hershey, G.K., Friedrich, M.F., Esswein, L.A., Thomas, M.L., Chatila, T.A. N. Engl. J. Med. (1997) [Pubmed]
  14. Monocyte function in a severe combined immunodeficient patient with a donor splice site mutation in the Jak3 gene. Villa, A., Sironi, M., Macchi, P., Matteucci, C., Notarangelo, L.D., Vezzoni, P., Mantovani, A. Blood (1996) [Pubmed]
  15. Functional role of interleukin-4 (IL-4) and IL-7 in the development of X-linked severe combined immunodeficiency. Kumaki, S., Ishii, N., Minegishi, M., Tsuchiya, S., Cosman, D., Sugamura, K., Konno, T. Blood (1999) [Pubmed]
  16. Induction of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. Gingras, S., Moriggl, R., Groner, B., Simard, J. Mol. Endocrinol. (1999) [Pubmed]
  17. Inhibition of toxic shock syndrome toxin-1-induced cytokine production and T cell activation by interleukin-10, interleukin-4, and dexamethasone. Krakauer, T. J. Infect. Dis. (1995) [Pubmed]
  18. Serum interleukin 4 and interleukin 10 levels in patients with chronic hepatitis C virus infection. Reiser, M., Marousis, C.G., Nelson, D.R., Lauer, G., González-Peralta, R.P., Davis, G.L., Lau, J.Y. J. Hepatol. (1997) [Pubmed]
  19. Inhibition of NF-AT-dependent transcription by NF-kappa B: implications for differential gene expression in T helper cell subsets. Casolaro, V., Georas, S.N., Song, Z., Zubkoff, I.D., Abdulkadir, S.A., Thanos, D., Ono, S.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  20. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Howard, T.D., Koppelman, G.H., Xu, J., Zheng, S.L., Postma, D.S., Meyers, D.A., Bleecker, E.R. Am. J. Hum. Genet. (2002) [Pubmed]
  21. HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Wang, C., Tang, J., Song, W., Lobashevsky, E., Wilson, C.M., Kaslow, R.A. Hepatology (2004) [Pubmed]
  22. Interleukin 4 regulates phosphorylation of serine 756 in the transactivation domain of Stat6. Roles for multiple phosphorylation sites and Stat6 function. Wang, Y., Malabarba, M.G., Nagy, Z.S., Kirken, R.A. J. Biol. Chem. (2004) [Pubmed]
  23. A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4. Debinski, W., Obiri, N.I., Pastan, I., Puri, R.K. J. Biol. Chem. (1995) [Pubmed]
  24. Induction of lymphokine-activated killer activity by interleukin 4 in human lymphocytes preactivated by interleukin 2 in vivo or in vitro. Higuchi, C.M., Thompson, J.A., Lindgren, C.G., Gillis, S., Widmer, M.B., Kern, D.E., Fefer, A. Cancer Res. (1989) [Pubmed]
  25. JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering. Rolling, C., Treton, D., Beckmann, P., Galanaud, P., Richard, Y. Oncogene (1995) [Pubmed]
  26. Endogenous interleukin 6 plays an obligatory role in interleukin 4-dependent human IgE synthesis. Vercelli, D., Jabara, H.H., Arai, K., Yokota, T., Geha, R.S. Eur. J. Immunol. (1989) [Pubmed]
  27. Transforming growth factor beta 1 and interleukin 4 induced alpha smooth muscle actin expression and myofibroblast-like differentiation in human synovial fibroblasts in vitro: modulation by basic fibroblast growth factor. Mattey, D.L., Dawes, P.T., Nixon, N.B., Slater, H. Ann. Rheum. Dis. (1997) [Pubmed]
  28. The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production. Verhoef, C.M., van Roon, J.A., Vianen, M.E., Lafeber, F.P., Bijlsma, J.W. Ann. Rheum. Dis. (1999) [Pubmed]
  29. Phorbol ester, prostaglandin E2, forskolin and okadaic acid differentially modulate interleukin-4-versus interleukin-2-dependent immunoglobulin induction in human cellular models, in contrast to other selected modifiers of cellular activation. Armerding, D., Hren, A. Int. Arch. Allergy Immunol. (1993) [Pubmed]
  30. Roles for the interleukin-4 receptor and associated JAK/STAT proteins in human articular chondrocyte mechanotransduction. Millward-Sadler, S.J., Khan, N.S., Bracher, M.G., Wright, M.O., Salter, D.M. Osteoarthr. Cartil. (2006) [Pubmed]
  31. Modulation of apoptosis with cytokines in B-cell chronic lymphocytic leukaemia. Mainou-Fowler, T., Prentice, A.G. Leuk. Lymphoma (1996) [Pubmed]
  32. Monocyte cell surface glycosaminoglycans positively modulate IL-4-induced differentiation toward dendritic cells. den Dekker, E., Grefte, S., Huijs, T., ten Dam, G.B., Versteeg, E.M., van den Berk, L.C., Bladergroen, B.A., van Kuppevelt, T.H., Figdor, C.G., Torensma, R. J. Immunol. (2008) [Pubmed]
  33. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Lin, J.X., Migone, T.S., Tsang, M., Friedmann, M., Weatherbee, J.A., Zhou, L., Yamauchi, A., Bloom, E.T., Mietz, J., John, S. Immunity (1995) [Pubmed]
  34. Interleukin-13 receptor alpha' but not alpha chain: a functional component of interleukin-4 receptors. Murata, T., Taguchi, J., Puri, R.K. Blood (1998) [Pubmed]
  35. Interleukin-4 induces homotypic aggregation of human mast cells by promoting LFA-1/ICAM-1 adhesion molecules. Toru, H., Kinashi, T., Ra, C., Nonoyama, S., Yata, J., Nakahata, T. Blood (1997) [Pubmed]
  36. Binding of IL-4 to the IL-13Ralpha(1)/IL-4Ralpha receptor complex leads to STAT3 phosphorylation but not to its nuclear translocation. Wery-Zennaro, S., Letourneur, M., David, M., Bertoglio, J., Pierre, J. FEBS Lett. (1999) [Pubmed]
  37. Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis. Inoue, T., Kira, R., Nakao, F., Ihara, K., Bassuny, W.M., Kusuhara, K., Nihei, K., Takeshita, K., Hara, T. Arch. Neurol. (2002) [Pubmed]
  38. Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. Murata, T., Puri, R.K. Cell. Immunol. (1997) [Pubmed]
  39. STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Gooch, J.L., Christy, B., Yee, D. Neoplasia (2002) [Pubmed]
  40. Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. Verbsky, J.W., Bach, E.A., Fang, Y.F., Yang, L., Randolph, D.A., Fields, L.E. J. Biol. Chem. (1996) [Pubmed]
  41. Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide. Olejniczak, E.T., Zhou, M.M., Fesik, S.W. Biochemistry (1997) [Pubmed]
  42. Acute allergen-induced airway remodeling in atopic asthma. Phipps, S., Benyahia, F., Ou, T.T., Barkans, J., Robinson, D.S., Kay, A.B. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  43. Phenotypic modulation of the stromal reticular network in normal and neoplastic lymph nodes: tissue transglutaminase reveals coordinate regulation of multiple cell types. Thomazy, V.A., Vega, F., Medeiros, L.J., Davies, P.J., Jones, D. Am. J. Pathol. (2003) [Pubmed]
  44. Regulation of cytolytic cell populations from human peripheral blood by B cell stimulatory factor 1 (interleukin 4). Widmer, M.B., Acres, R.B., Sassenfeld, H.M., Grabstein, K.H. J. Exp. Med. (1987) [Pubmed]
  45. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. D'Andrea, A., Ma, X., Aste-Amezaga, M., Paganin, C., Trinchieri, G. J. Exp. Med. (1995) [Pubmed]
  46. Interleukin 8 (IL-8) selectively inhibits immunoglobulin E production induced by IL-4 in human B cells. Kimata, H., Yoshida, A., Ishioka, C., Lindley, I., Mikawa, H. J. Exp. Med. (1992) [Pubmed]
  47. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Punnonen, J., Aversa, G., Cocks, B.G., McKenzie, A.N., Menon, S., Zurawski, G., de Waal Malefyt, R., de Vries, J.E. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  48. Interleukin 4 signals through two related pathways. Pernis, A., Witthuhn, B., Keegan, A.D., Nelms, K., Garfein, E., Ihle, J.N., Paul, W.E., Pierce, J.H., Rothman, P. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  49. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Russell, S.M., Tayebi, N., Nakajima, H., Riedy, M.C., Roberts, J.L., Aman, M.J., Migone, T.S., Noguchi, M., Markert, M.L., Buckley, R.H., O'Shea, J.J., Leonard, W.J. Science (1995) [Pubmed]
  50. Interleukin 4 counteracts the interleukin 2-induced proliferation of monoclonal B cells. Karray, S., DeFrance, T., Merle-Béral, H., Banchereau, J., Debré, P., Galanaud, P. J. Exp. Med. (1988) [Pubmed]
  51. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. Leung, D.Y., Martin, R.J., Szefler, S.J., Sher, E.R., Ying, S., Kay, A.B., Hamid, Q. J. Exp. Med. (1995) [Pubmed]
  52. Interleukin 4 induces selective production of interleukin 6 from normal human B lymphocytes. Smeland, E.B., Blomhoff, H.K., Funderud, S., Shalaby, M.R., Espevik, T. J. Exp. Med. (1989) [Pubmed]
  53. Net inflammatory capacity of human septic shock plasma evaluated by a monocyte-based target cell assay: identification of interleukin-10 as a major functional deactivator of human monocytes. Brandtzaeg, P., Osnes, L., Ovstebø, R., Joø, G.B., Westvik, A.B., Kierulf, P. J. Exp. Med. (1996) [Pubmed]
  54. Meniere's disease and allergy: allergens and cytokines. Keles, E., Gödekmerdan, A., Kalidağ, T., Kaygusuz, I., Yalçin, S., Cengiz Alpay, H., Aral, M. The Journal of laryngology and otology. (2004) [Pubmed]
  55. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Ghoreschi, K., Thomas, P., Breit, S., Dugas, M., Mailhammer, R., van Eden, W., van der Zee, R., Biedermann, T., Prinz, J., Mack, M., Mrowietz, U., Christophers, E., Schlöndorff, D., Plewig, G., Sander, C.A., Röcken, M. Nat. Med. (2003) [Pubmed]
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