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. 1997 Sep;92(1):1–5. doi: 10.1046/j.1365-2567.1997.00348.x

Interleukin-10 rescues T cells from apoptotic cell death: association with an upregulation of Bcl-2.

S B Cohen 1, J B Crawley 1, M C Kahan 1, M Feldmann 1, B M Foxwell 1
PMCID: PMC1363973  PMID: 9370916

Abstract

We demonstrate that interleukin-10 (IL-10) can inhibit T-cell apoptosis. T cells, within a PBMC (peripheral blood mononuclear cell) population, were stimulated via the T-cell receptor and grown in the presence of IL-2. These cells had less apoptosis when in the continuous presence of IL-10, compared with cells grown in the absence of IL-10. Conversely, when stimulated and grown in the presence of neutralizing antibody of IL-10, there was an increase in T-cell apoptosis. The in vitro rescue from apoptotic cell death of other lymphoid cells, such as germinal centre B cells, has been shown by others to involve a Bcl-2 pathway. We therefore investigated whether IL-10 might affect the Bcl-2 expression on cultured T cells. By Western blotting we demonstrated that continuous exposure of IL-10 to T cells (within a PBMC population) enhanced the expression of Bcl-2. Furthermore, T cells protected from apoptotic cell death by IL-10 were indistinguishable from viable untreated cells in their ability to proliferate to either immobilized anti-CD3 or IL-2. Thus, we have shown that continuous culture of T cells in the presence of IL-10 will inhibit T-cell apoptosis because of, at least in part, the upregulation of Bcl-2, and this is associated with a normal proliferative function.

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Selected References

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  1. Akbar A. N., Borthwick N. J., Wickremasinghe R. G., Panayoitidis P., Pilling D., Bofill M., Krajewski S., Reed J. C., Salmon M. Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression. Eur J Immunol. 1996 Feb;26(2):294–299. doi: 10.1002/eji.1830260204. [DOI] [PubMed] [Google Scholar]
  2. Blazar B. R., Taylor P. A., Smith S., Vallera D. A. Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood. 1995 Feb 1;85(3):842–851. [PubMed] [Google Scholar]
  3. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  4. Cohen S. B. IL-10 and IL-3 synergize to cause proliferation of human T cells. Immunology. 1995 Jul;85(3):351–356. [PMC free article] [PubMed] [Google Scholar]
  5. Cohen S. B., Katsikis P. D., Chu C. Q., Thomssen H., Webb L. M., Maini R. N., Londei M., Feldmann M. High level of interleukin-10 production by the activated T cell population within the rheumatoid synovial membrane. Arthritis Rheum. 1995 Jul;38(7):946–952. doi: 10.1002/art.1780380710. [DOI] [PubMed] [Google Scholar]
  6. Cohen S. B., Katsikis P. D., Feldmann M., Londei M. IL-10 enhances expression of the IL-2 receptor alpha chain on T cells. Immunology. 1994 Nov;83(3):329–332. [PMC free article] [PubMed] [Google Scholar]
  7. Cohen S. B., Parry S. L., Feldmann M., Foxwell B. Autocrine and paracrine regulation of human T cell IL-10 production. J Immunol. 1997 Jun 15;158(12):5596–5602. [PubMed] [Google Scholar]
  8. Cush J. J., Splawski J. B., Thomas R., McFarlin J. E., Schulze-Koops H., Davis L. S., Fujita K., Lipsky P. E. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jan;38(1):96–104. doi: 10.1002/art.1780380115. [DOI] [PubMed] [Google Scholar]
  9. Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
  10. Ding L., Shevach E. M. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992 May 15;148(10):3133–3139. [PubMed] [Google Scholar]
  11. 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]
  12. Firestein G. S., Yeo M., Zvaifler N. J. Apoptosis in rheumatoid arthritis synovium. J Clin Invest. 1995 Sep;96(3):1631–1638. doi: 10.1172/JCI118202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Katsikis P. D., Chu C. Q., Brennan F. M., Maini R. N., Feldmann M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med. 1994 May 1;179(5):1517–1527. doi: 10.1084/jem.179.5.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Levy Y., Brouet J. C. Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest. 1994 Jan;93(1):424–428. doi: 10.1172/JCI116977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Liu Y. J., Mason D. Y., Johnson G. D., Abbot S., Gregory C. D., Hardie D. L., Gordon J., MacLennan I. C. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991 Aug;21(8):1905–1910. doi: 10.1002/eji.1830210819. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Mower D. A., Jr, Peckham D. W., Illera V. A., Fishbaugh J. K., Stunz L. L., Ashman R. F. Decreased membrane phospholipid packing and decreased cell size precede DNA cleavage in mature mouse B cell apoptosis. J Immunol. 1994 May 15;152(10):4832–4842. [PubMed] [Google Scholar]
  18. Mueller D. L., Seiffert S., Fang W., Behrens T. W. Differential regulation of bcl-2 and bcl-x by CD3, CD28, and the IL-2 receptor in cloned CD4+ helper T cells. A model for the long-term survival of memory cells. J Immunol. 1996 Mar 1;156(5):1764–1771. [PubMed] [Google Scholar]
  19. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  20. Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
  21. Schlaak J. F., Hermann E., Gallati H., Meyer zum Büschenfelde K. H., Fleischer B. Differential effects of IL-10 on proliferation and cytokine production of human gamma/delta and alpha/beta T cells. Scand J Immunol. 1994 Feb;39(2):209–215. doi: 10.1111/j.1365-3083.1994.tb03362.x. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Taga K., Chretien J., Cherney B., Diaz L., Brown M., Tosato G. Interleukin-10 inhibits apoptotic cell death in infectious mononucleosis T cells. J Clin Invest. 1994 Jul;94(1):251–260. doi: 10.1172/JCI117315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Taga K., Mostowski H., Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood. 1993 Jun 1;81(11):2964–2971. [PubMed] [Google Scholar]
  25. Taga K., Tosato G. IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol. 1992 Feb 15;148(4):1143–1148. [PubMed] [Google Scholar]
  26. Wogensen L., Huang X., Sarvetnick N. Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med. 1993 Jul 1;178(1):175–185. doi: 10.1084/jem.178.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wogensen L., Lee M. S., Sarvetnick N. Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice. J Exp Med. 1994 Apr 1;179(4):1379–1384. doi: 10.1084/jem.179.4.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]

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