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Gene Review

IL4R  -  interleukin 4 receptor

Homo sapiens

Synonyms: 582J2.1, CD124, IL-4 receptor subunit alpha, IL-4R subunit alpha, IL-4R-alpha, ...
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Disease relevance of IL4R

  • To evaluate antitumor activity, nude mice carrying s.c. tumors composed of IL4R-bearing human A431 epidermoid carcinoma cells were injected with recombinant toxins i.v. every other day for three doses [1].
  • IL4(38-37)-PE38KDEL and IL4-PE38KDEL exhibited similar toxicity and pharmacokinetics in the mice, indicating that the improved antitumor activity of the circularly permuted IL4-toxin was due to its improved binding to the IL4R on the target cells [1].
  • We have targeted IL4R on a human solid tumor xenograft with chimeric proteins composed of human IL4 (hIL4) and 2 different mutant forms of a powerful bacterial toxin, Pseudomonas exotoxin A (PE) [2].
  • The observation that IL-2R gamma is a functional component of the IL-4 receptor, together with the finding that IL-2R gamma associates with the IL-7 receptor, begins to elucidate why deficiency of this common gamma chain (gamma c) has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency [3].
  • Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin [4].

High impact information on IL4R


Chemical compound and disease context of IL4R

  • Kay and co-workers in this issue of Leukemia Research have targeted interleukin-4 receptors (IL4R) on CLL B cells with a recombinant IL4 pseudomonas exotoxin fusion protein (IL-4(38--37)-PE38KDEL) [10].
  • The fall in serum IL-4 seen during the grass pollen season in the hayfever patients may reflect allergen driven upregulation of membrane IL-4 receptor expression or sequestration of cytokine producing cells to inflammatory sites [11].
  • We have utilized a mouse model of the Bernard-Soulier syndrome to engineer platelets expressing an alpha-subunit of GP Ib (GP Ibalpha) in which most of the extracytoplasmic sequence has been replaced by an isolated domain of the alpha-subunit of the human interleukin-4 receptor (IL-4Ralpha) [12].

Biological context of IL4R


Anatomical context of IL4R


Associations of IL4R with chemical compounds

  • Differences in IL4 signalling are likely due to crosstalk between integrin and cytokine signalling pathways, and not differences in IL4R expression [17].
  • Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits [22].
  • DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing [23].
  • However, activation of Ca(2+)-dependent pathways with A23187 or stimulation with IL-4 had no effect on the IL-4R expression [24].
  • Activation of protein kinase C-dependent pathways with phorbol myristate acetate (PMA) or activation of protein kinase A-dependent pathways with DBcAMP and prostaglandin E2 resulted in an augmented IL-4R expression at mRNA and protein level [24].

Physical interactions of IL4R

  • Unlabeled IL-13 competed successfully for IL-4 binding at 65 to 75 kD but was unable to completely displace Il-4 from its binding to the IL-4R alpha [20].
  • Through a deletion analysis of the IL-4R we have identified a putative FES-binding site in the cytoplasmic domain of the IL-4R [25].
  • RESULTS: SHP-2 bound IL-4Ralpha synthetic peptide; this binding was reduced in the presence of the R551 variant [26].
  • Co-expression of the cloned cDNA with that of IL-4R alpha resulted in a receptor complex that displayed high affinity for IL-13 (Kd approximately 30 pM), and that allowed cross-competition of IL-13 and IL-4 [27].
  • Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide [28].

Enzymatic interactions of IL4R


Regulatory relationships of IL4R


Other interactions of IL4R

  • Murine L929 cells, which do not express the gamma common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation [19].
  • A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected [16].
  • Thus, Stat6 activation by PV is an IL-4Ralpha-mediated, Jak1-dependent event that is independent of receptor dimerization [19].
  • JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering [13].
  • We have found that CD40-mediated signals cause a fivefold upregulation of IL-4 receptor (IL-4R) on the B cell surface and that this is associated with a 100-1000-fold increase in the cells' responsiveness to the cytokine [34].

Analytical, diagnostic and therapeutic context of IL4R


  1. Increased antitumor activity of a circularly permuted interleukin 4-toxin in mice with interleukin 4 receptor-bearing human carcinoma. Kreitman, R.J., Puri, R.K., Pastan, I. Cancer Res. (1995) [Pubmed]
  2. Interleukin-4 receptors expressed on tumor cells may serve as a target for anticancer therapy using chimeric Pseudomonas exotoxin. Debinski, W., Puri, R.K., Pastan, I. Int. J. Cancer (1994) [Pubmed]
  3. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Russell, S.M., Keegan, A.D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P., Friedmann, M.C., Miyajima, A., Puri, R.K., Paul, W.E. Science (1993) [Pubmed]
  4. Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin. Daley, T., Metcalfe, D.D., Akin, C. Blood (2001) [Pubmed]
  5. The IL-4 receptor: signaling mechanisms and biologic functions. Nelms, K., Keegan, A.D., Zamorano, J., Ryan, J.J., Paul, W.E. Annu. Rev. Immunol. (1999) [Pubmed]
  6. Genomic maps and comparative analysis of histone modifications in human and mouse. Bernstein, B.E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D.K., Huebert, D.J., McMahon, S., Karlsson, E.K., Kulbokas, E.J., Gingeras, T.R., Schreiber, S.L., Lander, E.S. Cell (2005) [Pubmed]
  7. Atopy and a mutation in the interleukin-4 receptor gene. Dupre, D., Audrezet, M.P., Ferec, C. N. Engl. J. Med. (2000) [Pubmed]
  8. Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Hage, T., Sebald, W., Reinemer, P. Cell (1999) [Pubmed]
  9. The interleukin-4 receptor variant Q576R in hyper-IgE syndrome. Grimbacher, B., Holland, S.M., Puck, J.M. N. Engl. J. Med. (1998) [Pubmed]
  10. CLL immunotoxins. Frankel, A.E., Kreitman, R.J. Leuk. Res. (2005) [Pubmed]
  11. Seasonal variation in interleukin 4 in patients with hayfever. Jones, K.P., Morris, R.H., Rolf, S., Davies, B.H. Cytokine (2000) [Pubmed]
  12. Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome. Kanaji, T., Russell, S., Ware, J. Blood (2002) [Pubmed]
  13. 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]
  14. No association between atopy/asthma and the ILe50Val polymorphism of IL-4 receptor. Noguchi, E., Shibasaki, M., Arinami, T., Takeda, K., Yokouchi, Y., Kobayashi, K., Imoto, N., Nakahara, S., Matsui, A., Hamaguchi, H. Am. J. Respir. Crit. Care Med. (1999) [Pubmed]
  15. A novel polymorphism in the 5' promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Hackstein, H., Hecker, M., Kruse, S., Bohnert, A., Ober, C., Deichmann, K.A., Bein, G. Immunogenetics (2001) [Pubmed]
  16. 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]
  17. 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]
  18. Growth factor receptor expression varies among high-grade gliomas and normal brain: epidermal growth factor receptor has excellent properties for interstitial fusion protein therapy. Liu, T.F., Tatter, S.B., Willingham, M.C., Yang, M., Hu, J.J., Frankel, A.E. Mol. Cancer Ther. (2003) [Pubmed]
  19. Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. Haque, S.J., Wu, Q., Kammer, W., Friedrich, K., Smith, J.M., Kerr, I.M., Stark, G.R., Williams, B.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  20. Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain. Schnyder, B., Lugli, S., Feng, N., Etter, H., Lutz, R.A., Ryffel, B., Sugamura, K., Wunderli-Allenspach, H., Moser, R. Blood (1996) [Pubmed]
  21. The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression. Reichel, M., Nelson, B.H., Greenberg, P.D., Rothman, P.B. J. Immunol. (1997) [Pubmed]
  22. Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits. Moriggl, R., Erhardt, I., Kammer, W., Berchtold, S., Schnarr, B., Lischke, A., Groner, B., Friedrich, K. Eur. J. Biochem. (1998) [Pubmed]
  23. Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome. Tenbrock, K., Schubert, A., Stapenhorst, L., Kemper, M.J., Gellermann, J., Timmermann, K., Müller-Wiefel, D.E., Querfeld, U., Hoppe, B., Michalk, D. Clin. Sci. (2002) [Pubmed]
  24. Interleukin-4 receptor regulation in human monocytic cells. de Wit, H., Hendriks, D.W., Halie, M.R., Vellenga, E. Blood (1994) [Pubmed]
  25. Interaction of the c-fes proto-oncogene product with the interleukin-4 receptor. Izuhara, K., Feldman, R.A., Greer, P., Harada, N. J. Biol. Chem. (1994) [Pubmed]
  26. Distinct signal transduction processes by IL-4 and IL-13 and influences from the Q551R variant of the human IL-4 receptor alpha chain. Kruse, S., Braun, S., Deichmann, K.A. Respir. Res. (2002) [Pubmed]
  27. Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex. Miloux, B., Laurent, P., Bonnin, O., Lupker, J., Caput, D., Vita, N., Ferrara, P. FEBS Lett. (1997) [Pubmed]
  28. 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]
  29. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain. Zhou, M.M., Huang, B., Olejniczak, E.T., Meadows, R.P., Shuker, S.B., Miyazaki, M., Trüb, T., Shoelson, S.E., Fesik, S.W. Nat. Struct. Biol. (1996) [Pubmed]
  30. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. Smerz-Bertling, C., Duschl, A. J. Biol. Chem. (1995) [Pubmed]
  31. Endogenous interferon-alpha production by differentiating human monocytes regulates expression and function of the IL-2/IL-4 receptor gamma chain. Bonder, C.S., Davies, K.V., Liu, X., Hertzog, P.J., Woodcock, J.M., Finlay-Jones, J.J., Hart, P.H. Cytokine (2002) [Pubmed]
  32. Epidermal growth factor regulates astrocyte expression of the interleukin-4 receptor via a MAPK-independent pathway. Barna, B.P., Mattera, R., Jacobs, B.S., Drazba, J., Estes, M.E., Prayson, R.A., Barnett, G.H. Cell. Immunol. (2001) [Pubmed]
  33. Characterization and regulation of interleukin-4 receptor in adult T-cell leukemia cells. Mori, N., Shirakawa, F., Murakami, S., Oda, S., Eto, S. Eur. J. Haematol. (1996) [Pubmed]
  34. CD40-mediated regulation of interleukin-4 signaling pathways in B lymphocytes. Siepmann, K., Wohlleben, G., Gray, D. Eur. J. Immunol. (1996) [Pubmed]
  35. Molecular cloning of a cDNA encoding the human interleukin 4 receptor. Galizzi, J.P., Zuber, C.E., Harada, N., Gorman, D.M., Djossou, O., Kastelein, R., Banchereau, J., Howard, M., Miyajima, A. Int. Immunol. (1990) [Pubmed]
  36. Detection of and discrimination between total and free human interleukin-4 and free soluble interleukin-4 receptor by ELISA. Jung, T., Bews, J.P., Enssle, K.H., Wagner, K., Neumann, C., Heusser, C.H. J. Immunol. Methods (1998) [Pubmed]
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