Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1995 Sep;15(9):5043–5053. doi: 10.1128/mcb.15.9.5043

Functional regions of the mouse interleukin-10 receptor cytoplasmic domain.

A S Ho 1, S H Wei 1, A L Mui 1, A Miyajima 1, K W Moore 1
PMCID: PMC230751  PMID: 7544437

Abstract

The functions of wild-type and mutant mouse interleukin-10 receptors (mIL-10R) expressed in murine Ba/F3 cells were studied. As observed previously, IL-10 stimulates proliferation of IL-10R-expressing Ba/F3 cells. Accumulation of viable cells in the proliferation assay is to a significant extent balanced by concomitant cell death. Moreover, growth in IL-10 also induces a previously unrecognized response, differentiation of the cells, as evidenced both by formation of large clusters of cells in cultures with IL-10 and by induction or enhancement of expression of several cell surface antigens, including CD32/16, CD2, LECAM-1 (v-selectin), and heat-stable antigen. Two distinct functional regions near the C terminus of the mIL-10R cytoplasmic domain which mediate proliferation were identified; one of these regions also mediates the differentiation response. A third region proximal to the transmembrane domain was identified; removal of this region renders the cell 10- to 100-fold more sensitive to IL-10 in the proliferation assay. In cells expressing both wild-type and mutant IL-10R, stimulation with IL-10 leads to tyrosine phosphorylation of the kinases JAK1 and TYK2 but not JAK2 or JAK3 under the conditions tested.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chen W. F., Zlotnik A. IL-10: a novel cytotoxic T cell differentiation factor. J Immunol. 1991 Jul 15;147(2):528–534. [PubMed] [Google Scholar]
  2. D'Andrea A. D., Yoshimura A., Youssoufian H., Zon L. I., Koo J. W., Lodish H. F. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991 Apr;11(4):1980–1987. doi: 10.1128/mcb.11.4.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elliott J. F., Albrecht G. R., Gilladoga A., Handunnetti S. M., Neequaye J., Lallinger G., Minjas J. N., Howard R. J. Genes for Plasmodium falciparum surface antigens cloned by expression in COS cells. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6363–6367. doi: 10.1073/pnas.87.16.6363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Farrar M. A., Campbell J. D., Schreiber R. D. Identification of a functionally important sequence in the C terminus of the interferon-gamma receptor. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11706–11710. doi: 10.1073/pnas.89.24.11706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Farrar M. A., Fernandez-Luna J., Schreiber R. D. Identification of two regions within the cytoplasmic domain of the human interferon-gamma receptor required for function. J Biol Chem. 1991 Oct 15;266(29):19626–19635. [PubMed] [Google Scholar]
  8. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fluckiger A. C., Durand I., Banchereau J. Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells. J Exp Med. 1994 Jan 1;179(1):91–99. doi: 10.1084/jem.179.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fukunaga R., Ishizaka-Ikeda E., Nagata S. Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony-stimulating factor receptor. Cell. 1993 Sep 24;74(6):1079–1087. doi: 10.1016/0092-8674(93)90729-a. [DOI] [PubMed] [Google Scholar]
  11. Geng Y., Gulbins E., Altman A., Lotz M. Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8602–8606. doi: 10.1073/pnas.91.18.8602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Greenlund A. C., Farrar M. A., Viviano B. L., Schreiber R. D. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 1994 Apr 1;13(7):1591–1600. doi: 10.1002/j.1460-2075.1994.tb06422.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ho A. S., Liu Y., Khan T. A., Hsu D. H., Bazan J. F., Moore K. W. A receptor for interleukin 10 is related to interferon receptors. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11267–11271. doi: 10.1073/pnas.90.23.11267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ho A. S., Moore K. W. Interleukin-10 and its receptor. Ther Immunol. 1994 Jun;1(3):173–185. [PubMed] [Google Scholar]
  16. 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]
  17. Larner A. C., David M., Feldman G. M., Igarashi K., Hackett R. H., Webb D. S., Sweitzer S. M., Petricoin E. F., 3rd, Finbloom D. S. Tyrosine phosphorylation of DNA binding proteins by multiple cytokines. Science. 1993 Sep 24;261(5129):1730–1733. doi: 10.1126/science.8378773. [DOI] [PubMed] [Google Scholar]
  18. Lehmann J., Seegert D., Strehlow I., Schindler C., Lohmann-Matthes M. L., Decker T. IL-10-induced factors belonging to the p91 family of proteins bind to IFN-gamma-responsive promoter elements. J Immunol. 1994 Jul 1;153(1):165–172. [PubMed] [Google Scholar]
  19. Liu Y., Wei S. H., Ho A. S., de Waal Malefyt R., Moore K. W. Expression cloning and characterization of a human IL-10 receptor. J Immunol. 1994 Feb 15;152(4):1821–1829. [PubMed] [Google Scholar]
  20. MacNeil I. A., Suda T., Moore K. W., Mosmann T. R., Zlotnik A. IL-10, a novel growth cofactor for mature and immature T cells. J Immunol. 1990 Dec 15;145(12):4167–4173. [PubMed] [Google Scholar]
  21. MacNeil I., Kennedy J., Godfrey D. I., Jenkins N. A., Masciantonio M., Mineo C., Gilbert D. J., Copeland N. G., Boyd R. L., Zlotnik A. Isolation of a cDNA encoding thymic shared antigen-1. A new member of the Ly6 family with a possible role in T cell development. J Immunol. 1993 Dec 15;151(12):6913–6923. [PubMed] [Google Scholar]
  22. 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]
  23. Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  24. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  25. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  26. Narazaki M., Witthuhn B. A., Yoshida K., Silvennoinen O., Yasukawa K., Ihle J. N., Kishimoto T., Taga T. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2285–2289. doi: 10.1073/pnas.91.6.2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Quelle F. W., Sato N., Witthuhn B. A., Inhorn R. C., Eder M., Miyajima A., Griffin J. D., Ihle J. N. JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol. 1994 Jul;14(7):4335–4341. doi: 10.1128/mcb.14.7.4335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sakamaki K., Miyajima I., Kitamura T., Miyajima A. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J. 1992 Oct;11(10):3541–3549. doi: 10.1002/j.1460-2075.1992.tb05437.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sakamaki K., Wang H. M., Miyajima I., Kitamura T., Todokoro K., Harada N., Miyajima A. Ligand-dependent activation of chimeric receptors with the cytoplasmic domain of the interleukin-3 receptor beta subunit (beta IL3). J Biol Chem. 1993 Jul 25;268(21):15833–15839. [PubMed] [Google Scholar]
  31. Sato N., Sakamaki K., Terada N., Arai K., Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J. 1993 Nov;12(11):4181–4189. doi: 10.1002/j.1460-2075.1993.tb06102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Silvennoinen O., Witthuhn B. A., Quelle F. W., Cleveland J. L., Yi T., Ihle J. N. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8429–8433. doi: 10.1073/pnas.90.18.8429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Suda T., O'Garra A., MacNeil I., Fischer M., Bond M. W., Zlotnik A. Identification of a novel thymocyte growth-promoting factor derived from B cell lymphomas. Cell Immunol. 1990 Aug;129(1):228–240. doi: 10.1016/0008-8749(90)90200-b. [DOI] [PubMed] [Google Scholar]
  34. Taga K., Cherney B., Tosato G. IL-10 inhibits apoptotic cell death in human T cells starved of IL-2. Int Immunol. 1993 Dec;5(12):1599–1608. doi: 10.1093/intimm/5.12.1599. [DOI] [PubMed] [Google Scholar]
  35. Tan J. C., Indelicato S. R., Narula S. K., Zavodny P. J., Chou C. C. Characterization of interleukin-10 receptors on human and mouse cells. J Biol Chem. 1993 Oct 5;268(28):21053–21059. [PubMed] [Google Scholar]
  36. Theroux S. J., Stanley K., Campbell D. A., Davis R. J. Mutational removal of the major site of serine phosphorylation of the epidermal growth factor receptor causes potentiation of signal transduction: role of receptor down-regulation. Mol Endocrinol. 1992 Nov;6(11):1849–1857. doi: 10.1210/mend.6.11.1480174. [DOI] [PubMed] [Google Scholar]
  37. Thompson-Snipes L., Dhar V., Bond M. W., Mosmann T. R., Moore K. W., Rennick D. M. Interleukin 10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med. 1991 Feb 1;173(2):507–510. doi: 10.1084/jem.173.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Unkeless J. C. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 1979 Sep 19;150(3):580–596. doi: 10.1084/jem.150.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Watling D., Guschin D., Müller M., Silvennoinen O., Witthuhn B. A., Quelle F. W., Rogers N. C., Schindler C., Stark G. R., Ihle J. N. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature. 1993 Nov 11;366(6451):166–170. doi: 10.1038/366166a0. [DOI] [PubMed] [Google Scholar]
  41. Weber-Nordt R. M., Meraz M. A., Schreiber R. D. Lipopolysaccharide-dependent induction of IL-10 receptor expression on murine fibroblasts. J Immunol. 1994 Oct 15;153(8):3734–3744. [PubMed] [Google Scholar]
  42. 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]
  43. Yokota T., Lee F., Rennick D., Hall C., Arai N., Mosmann T., Nabel G., Cantor H., Arai K. Isolation and characterization of a mouse cDNA clone that expresses mast-cell growth-factor activity in monkey cells. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1070–1074. doi: 10.1073/pnas.81.4.1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. te Velde A. A., de Waal Malefijt R., Huijbens R. J., de Vries J. E., Figdor C. G. IL-10 stimulates monocyte Fc gamma R surface expression and cytotoxic activity. Distinct regulation of antibody-dependent cellular cytotoxicity by IFN-gamma, IL-4, and IL-10. J Immunol. 1992 Dec 15;149(12):4048–4052. [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES