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. 1996 Nov 1;319(Pt 3):865–872. doi: 10.1042/bj3190865

Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-gamma and interleukin-4 receptor-alpha.

M G Malabarba 1, H Rui 1, H H Deutsch 1, J Chung 1, F S Kalthoff 1, W L Farrar 1, R A Kirken 1
PMCID: PMC1217868  PMID: 8920992

Abstract

The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and IL15 use the common IL2 receptor-gamma (IL2R gamma) and activate the IL2R gamma-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is structurally related to IL4, competes with IL4 for binding to cell surface receptors and exhibits many similar biological effects. The molecular basis for this functional overlap between IL4 and IL13 has been attributed mainly to a shared use of the 140 kDa IL4R alpha, since these cytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2R gamma or JAK3. This notion has been supported by the identification of a novel 70 kDa IL13 receptor in certain IL13-responsive cell lines that lack IL2R gamma. The present study sheds new light on the issue of functional overlap between IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2R gamma and IL4R alpha, IL13 can mimic IL4-induced heterodimerization of IL2R gamma and IL4R alpha, with consequent marked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines require the simultaneous presence of IL4R alpha and IL2R gamma to mediate JAK3 and proliferative responses, and analysis of 12 IL4R alpha variants showed that IL4 and IL13 signals were equally affected by mutations of the cytoplasmic domain. We conclude that IL13 activates the IL2R gamma-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor subunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contributes to the severe combined immuno-deficiency syndromes associated with inactivation of the IL2R gamma or JAK3 genes.

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Selected References

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  1. Argetsinger L. S., Campbell G. S., Yang X., Witthuhn B. A., Silvennoinen O., Ihle J. N., Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell. 1993 Jul 30;74(2):237–244. doi: 10.1016/0092-8674(93)90415-m. [DOI] [PubMed] [Google Scholar]
  2. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  3. Deutsch H. H., Koettnitz K., Chung J., Kalthoff F. S. Distinct sequence motifs within the cytoplasmic domain of the human IL-4 receptor differentially regulate apoptosis inhibition and cell growth. J Immunol. 1995 Apr 15;154(8):3696–3703. [PubMed] [Google Scholar]
  4. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. He Y. W., Malek T. R. The IL-2 receptor gamma c chain does not function as a subunit shared by the IL-4 and IL-13 receptors. Implication for the structure of the IL-4 receptor. J Immunol. 1995 Jul 1;155(1):9–12. [PubMed] [Google Scholar]
  6. Hilton D. J., Zhang J. G., Metcalf D., Alexander W. S., Nicola N. A., Willson T. A. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):497–501. doi: 10.1073/pnas.93.1.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M., McKnight S. L. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. doi: 10.1126/science.8085155. [DOI] [PubMed] [Google Scholar]
  8. Izuhara K., Heike T., Otsuka T., Yamaoka K., Mayumi M., Imamura T., Niho Y., Harada N. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients. J Biol Chem. 1996 Jan 12;271(2):619–622. doi: 10.1074/jbc.271.2.619. [DOI] [PubMed] [Google Scholar]
  9. Keegan A. D., Johnston J. A., Tortolani P. J., McReynolds L. J., Kinzer C., O'Shea J. J., Paul W. E. Similarities and differences in signal transduction by interleukin 4 and interleukin 13: analysis of Janus kinase activation. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7681–7685. doi: 10.1073/pnas.92.17.7681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kimura Y., Takeshita T., Kondo M., Ishii N., Nakamura M., Van Snick J., Sugamura K. Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex. Int Immunol. 1995 Jan;7(1):115–120. doi: 10.1093/intimm/7.1.115. [DOI] [PubMed] [Google Scholar]
  11. Kirken R. A., Rui H., Evans G. A., Farrar W. L. Characterization of an interleukin-2 (IL-2)-induced tyrosine phosphorylated 116-kDa protein associated with the IL-2 receptor beta-subunit. J Biol Chem. 1993 Oct 25;268(30):22765–22770. [PubMed] [Google Scholar]
  12. Kirken R. A., Rui H., Howard O. M., Farrar W. L. Involvement of JAK-family tyrosine kinases in hematopoietin receptor signal transduction. Prog Growth Factor Res. 1994;5(2):195–211. doi: 10.1016/0955-2235(94)90005-1. [DOI] [PubMed] [Google Scholar]
  13. Kirken R. A., Rui H., Malabarba M. G., Farrar W. L. Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. J Biol Chem. 1994 Jul 22;269(29):19136–19141. [PubMed] [Google Scholar]
  14. Kirken R. A., Rui H., Malabarba M. G., Howard O. M., Kawamura M., O'Shea J. J., Farrar W. L. Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain. Cytokine. 1995 Oct;7(7):689–700. doi: 10.1006/cyto.1995.0081. [DOI] [PubMed] [Google Scholar]
  15. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  16. Kitamura T., Tange T., Terasawa T., Chiba S., Kuwaki T., Miyagawa K., Piao Y. F., Miyazono K., Urabe A., Takaku F. Establishment and characterization of a unique human cell line that proliferates dependently on GM-CSF, IL-3, or erythropoietin. J Cell Physiol. 1989 Aug;140(2):323–334. doi: 10.1002/jcp.1041400219. [DOI] [PubMed] [Google Scholar]
  17. Koettnitz K., Kalthoff F. S. Human interleukin-4 receptor signaling requires sequences contained within two cytoplasmic regions. Eur J Immunol. 1993 Apr;23(4):988–991. doi: 10.1002/eji.1830230437. [DOI] [PubMed] [Google Scholar]
  18. Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K., Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  19. Kumaki S., Kondo M., Takeshita T., Asao H., Nakamura M., Sugamura K. Cloning of the mouse interleukin 2 receptor gamma chain: demonstration of functional differences between the mouse and human receptors. Biochem Biophys Res Commun. 1993 May 28;193(1):356–363. doi: 10.1006/bbrc.1993.1631. [DOI] [PubMed] [Google Scholar]
  20. Lefort S., Vita N., Reeb R., Caput D., Ferrara P. IL-13 and IL-4 share signal transduction elements as well as receptor components in TF-1 cells. FEBS Lett. 1995 Jun 12;366(2-3):122–126. doi: 10.1016/0014-5793(95)00512-8. [DOI] [PubMed] [Google Scholar]
  21. Lin J. X., Migone T. S., Tsang M., Friedmann M., Weatherbee J. A., Zhou L., Yamauchi A., Bloom E. T., Mietz J., John S. 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. Immunity. 1995 Apr;2(4):331–339. doi: 10.1016/1074-7613(95)90141-8. [DOI] [PubMed] [Google Scholar]
  22. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  23. Macchi P., Villa A., Giliani S., Sacco M. G., Frattini A., Porta F., Ugazio A. G., Johnston J. A., Candotti F., O'Shea J. J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65–68. doi: 10.1038/377065a0. [DOI] [PubMed] [Google Scholar]
  24. Malabarba M. G., Kirken R. A., Rui H., Koettnitz K., Kawamura M., O'Shea J. J., Kalthoff F. S., Farrar W. L. Activation of JAK3, but not JAK1, is critical to interleukin-4 (IL4) stimulated proliferation and requires a membrane-proximal region of IL4 receptor alpha. J Biol Chem. 1995 Apr 21;270(16):9630–9637. doi: 10.1074/jbc.270.16.9630. [DOI] [PubMed] [Google Scholar]
  25. Matthews D. J., Clark P. A., Herbert J., Morgan G., Armitage R. J., Kinnon C., Minty A., Grabstein K. H., Caput D., Ferrara P. Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15. Blood. 1995 Jan 1;85(1):38–42. [PubMed] [Google Scholar]
  26. McKenzie A. N., Culpepper J. A., de Waal Malefyt R., Brière F., Punnonen J., Aversa G., Sato A., Dang W., Cocks B. G., Menon S. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3735–3739. doi: 10.1073/pnas.90.8.3735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Minty A., Chalon P., Derocq J. M., Dumont X., Guillemot J. C., Kaghad M., Labit C., Leplatois P., Liauzun P., Miloux B. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993 Mar 18;362(6417):248–250. doi: 10.1038/362248a0. [DOI] [PubMed] [Google Scholar]
  28. Miyazaki T., Kawahara A., Fujii H., Nakagawa Y., Minami Y., Liu Z. J., Oishi I., Silvennoinen O., Witthuhn B. A., Ihle J. N. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994 Nov 11;266(5187):1045–1047. doi: 10.1126/science.7973659. [DOI] [PubMed] [Google Scholar]
  29. Murakami M., Hibi M., Nakagawa N., Nakagawa T., Yasukawa K., Yamanishi K., Taga T., Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993 Jun 18;260(5115):1808–1810. doi: 10.1126/science.8511589. [DOI] [PubMed] [Google Scholar]
  30. Murata T., Noguchi P. D., Puri R. K. IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. J Immunol. 1996 Apr 15;156(8):2972–2978. [PubMed] [Google Scholar]
  31. Murata T., Noguchi P. D., Puri R. K. Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. J Biol Chem. 1995 Dec 22;270(51):30829–30836. doi: 10.1074/jbc.270.51.30829. [DOI] [PubMed] [Google Scholar]
  32. Noguchi M., Nakamura Y., Russell S. M., Ziegler S. F., Tsang M., Cao X., Leonard W. J. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. doi: 10.1126/science.8266077. [DOI] [PubMed] [Google Scholar]
  33. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  34. O'Neal K. D., Yu-Lee L. Y. The proline-rich motif (PRM): a novel feature of the cytokine/hematopoietin receptor superfamily. Lymphokine Cytokine Res. 1993 Oct;12(5):309–312. [PubMed] [Google Scholar]
  35. Obiri N. I., Debinski W., Leonard W. J., Puri R. K. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem. 1995 Apr 14;270(15):8797–8804. doi: 10.1074/jbc.270.15.8797. [DOI] [PubMed] [Google Scholar]
  36. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
  37. Punnonen J., Aversa G., Cocks B. G., McKenzie A. N., Menon S., Zurawski G., de Waal Malefyt R., de Vries J. E. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730–3734. doi: 10.1073/pnas.90.8.3730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rui H., Djeu J. Y., Evans G. A., Kelly P. A., Farrar W. L. Prolactin receptor triggering. Evidence for rapid tyrosine kinase activation. J Biol Chem. 1992 Nov 25;267(33):24076–24081. [PubMed] [Google Scholar]
  39. Rui H., Kirken R. A., Farrar W. L. Activation of receptor-associated tyrosine kinase JAK2 by prolactin. J Biol Chem. 1994 Feb 18;269(7):5364–5368. [PubMed] [Google Scholar]
  40. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  41. 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. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. doi: 10.1126/science.8266078. [DOI] [PubMed] [Google Scholar]
  42. Smerz-Bertling C., Duschl A. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. J Biol Chem. 1995 Jan 13;270(2):966–970. doi: 10.1074/jbc.270.2.966. [DOI] [PubMed] [Google Scholar]
  43. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  44. Stahl N., Yancopoulos G. D. The alphas, betas, and kinases of cytokine receptor complexes. Cell. 1993 Aug 27;74(4):587–590. doi: 10.1016/0092-8674(93)90506-l. [DOI] [PubMed] [Google Scholar]
  45. Tony H. P., Shen B. J., Reusch P., Sebald W. Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency. Eur J Biochem. 1994 Oct 15;225(2):659–665. doi: 10.1111/j.1432-1033.1994.00659.x. [DOI] [PubMed] [Google Scholar]
  46. Vita N., Lefort S., Laurent P., Caput D., Ferrara P. Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types. J Biol Chem. 1995 Feb 24;270(8):3512–3517. doi: 10.1074/jbc.270.8.3512. [DOI] [PubMed] [Google Scholar]
  47. Voss S. D., Sondel P. M., Robb R. J. Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R. J Exp Med. 1992 Aug 1;176(2):531–541. doi: 10.1084/jem.176.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wang L. M., Michieli P., Lie W. R., Liu F., Lee C. C., Minty A., Sun X. J., Levine A., White M. F., Pierce J. H. The insulin receptor substrate-1-related 4PS substrate but not the interleukin-2R gamma chain is involved in interleukin-13-mediated signal transduction. Blood. 1995 Dec 1;86(11):4218–4227. [PubMed] [Google Scholar]
  49. Welham M. J., Learmonth L., Bone H., Schrader J. W. Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. J Biol Chem. 1995 May 19;270(20):12286–12296. doi: 10.1074/jbc.270.20.12286. [DOI] [PubMed] [Google Scholar]
  50. Witthuhn B. A., Quelle F. W., Silvennoinen O., Yi T., Tang B., Miura O., Ihle J. N. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. doi: 10.1016/0092-8674(93)90414-l. [DOI] [PubMed] [Google Scholar]
  51. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  52. Zurawski G., de Vries J. E. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. doi: 10.1016/0167-5699(94)90021-3. [DOI] [PubMed] [Google Scholar]
  53. Zurawski S. M., Chomarat P., Djossou O., Bidaud C., McKenzie A. N., Miossec P., Banchereau J., Zurawski G. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J Biol Chem. 1995 Jun 9;270(23):13869–13878. doi: 10.1074/jbc.270.23.13869. [DOI] [PubMed] [Google Scholar]
  54. Zurawski S. M., Vega F., Jr, Huyghe B., Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993 Jul;12(7):2663–2670. doi: 10.1002/j.1460-2075.1993.tb05927.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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