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. 1996 Mar;64(3):913–918. doi: 10.1128/iai.64.3.913-918.1996

Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression.

J H Gong 1, M Zhang 1, R L Modlin 1, P S Linsley 1, D Iyer 1, Y Lin 1, P F Barnes 1
PMCID: PMC173856  PMID: 8641800

Abstract

To characterize the mechanism by which interleukin 10 (IL-10) inhibits Th1 responses to intracellular pathogens, we evaluated the interaction between IL-10 and Mycobacterium tuberculosis-induced gamma interferon (IFN-gamma) production by peripheral blood mononuclear cells from persons across the spectrum of tuberculous infection. M. tuberculosis-induced IFN-gamma production was highest in healthy tuberculin reactors, intermediate in human immunodeficiency virus (HIV)-negative tuberculosis patients, and lowest in HIV-infected tuberculosis patients. Neutralizing antibodies to IL-10 increased IFN-gamma production in HIV-infected and HIV-negative tuberculosis patients by enhancing monocyte IL-12 production. Expression of the T-cell-costimulatory molecule CTLA-4 was depressed in M. tuberculosis-stimulated peripheral blood mononuclear cells from tuberculosis patients, and anti-IL-10 and Il-12 upregulated expression of CTLA-4. These findings provide evidence that intracellular pathogens can inhibit Th1 responses and downregulate expression of specific costimulatory molecules.

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Selected References

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  1. Barnes P. F., Chatterjee D., Abrams J. S., Lu S., Wang E., Yamamura M., Brennan P. J., Modlin R. L. Cytokine production induced by Mycobacterium tuberculosis lipoarabinomannan. Relationship to chemical structure. J Immunol. 1992 Jul 15;149(2):541–547. [PubMed] [Google Scholar]
  2. Barnes P. F., Mistry S. D., Cooper C. L., Pirmez C., Rea T. H., Modlin R. L. Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleuritis. J Immunol. 1989 Feb 15;142(4):1114–1119. [PubMed] [Google Scholar]
  3. Bertagnolli M. M., Lin B. Y., Young D., Herrmann S. H. IL-12 augments antigen-dependent proliferation of activated T lymphocytes. J Immunol. 1992 Dec 15;149(12):3778–3783. [PubMed] [Google Scholar]
  4. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carvalho E. M., Bacellar O., Brownell C., Regis T., Coffman R. L., Reed S. G. Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis. J Immunol. 1994 Jun 15;152(12):5949–5956. [PubMed] [Google Scholar]
  6. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  8. Flores Villanueva P. O., Reiser H., Stadecker M. J. Regulation of T helper cell responses in experimental murine schistosomiasis by IL-10. Effect on expression of B7 and B7-2 costimulatory molecules by macrophages. J Immunol. 1994 Dec 1;153(11):5190–5199. [PubMed] [Google Scholar]
  9. Ghalib H. W., Piuvezam M. R., Skeiky Y. A., Siddig M., Hashim F. A., el-Hassan A. M., Russo D. M., Reed S. G. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest. 1993 Jul;92(1):324–329. doi: 10.1172/JCI116570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Holaday B. J., Pompeu M. M., Jeronimo S., Texeira M. J., Sousa A. de A., Vasconcelos A. W., Pearson R. D., Abrams J. S., Locksley R. M. Potential role for interleukin-10 in the immunosuppression associated with kala azar. J Clin Invest. 1993 Dec;92(6):2626–2632. doi: 10.1172/JCI116878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Holland S. M., Eisenstein E. M., Kuhns D. B., Turner M. L., Fleisher T. A., Strober W., Gallin J. I. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report. N Engl J Med. 1994 May 12;330(19):1348–1355. doi: 10.1056/NEJM199405123301904. [DOI] [PubMed] [Google Scholar]
  12. Kaufmann S. H. Immunity to intracellular microbial pathogens. Immunol Today. 1995 Jul;16(7):338–342. doi: 10.1016/0167-5699(95)80151-0. [DOI] [PubMed] [Google Scholar]
  13. Linsley P. S., Brady W., Urnes M., Grosmaire L. S., Damle N. K., Ledbetter J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Linsley P. S., Greene J. L., Tan P., Bradshaw J., Ledbetter J. A., Anasetti C., Damle N. K. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med. 1992 Dec 1;176(6):1595–1604. doi: 10.1084/jem.176.6.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nathan C. F., Kaplan G., Levis W. R., Nusrat A., Witmer M. D., Sherwin S. A., Job C. K., Horowitz C. R., Steinman R. M., Cohn Z. A. Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med. 1986 Jul 3;315(1):6–15. doi: 10.1056/NEJM198607033150102. [DOI] [PubMed] [Google Scholar]
  16. Sampaio E. P., Moreira A. L., Sarno E. N., Malta A. M., Kaplan G. Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med. 1992 Jun 1;175(6):1729–1737. doi: 10.1084/jem.175.6.1729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sieling P. A., Abrams J. S., Yamamura M., Salgame P., Bloom B. R., Rea T. H., Modlin R. L. Immunosuppressive roles for IL-10 and IL-4 in human infection. In vitro modulation of T cell responses in leprosy. J Immunol. 1993 Jun 15;150(12):5501–5510. [PubMed] [Google Scholar]
  18. Sieling P. A., Wang X. H., Gately M. K., Oliveros J. L., McHugh T., Barnes P. F., Wolf S. F., Golkar L., Yamamura M., Yogi Y. IL-12 regulates T helper type 1 cytokine responses in human infectious disease. J Immunol. 1994 Oct 15;153(8):3639–3647. [PubMed] [Google Scholar]
  19. Sundar S., Rosenkaimer F., Lesser M. L., Murray H. W. Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis. J Infect Dis. 1995 Apr;171(4):992–996. doi: 10.1093/infdis/171.4.992. [DOI] [PubMed] [Google Scholar]
  20. Sánchez F. O., Rodríguez J. I., Agudelo G., García L. F. Immune responsiveness and lymphokine production in patients with tuberculosis and healthy controls. Infect Immun. 1994 Dec;62(12):5673–5678. doi: 10.1128/iai.62.12.5673-5678.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  22. Yoshimoto T., Paul W. E. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med. 1994 Apr 1;179(4):1285–1295. doi: 10.1084/jem.179.4.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Zhang M., Gately M. K., Wang E., Gong J., Wolf S. F., Lu S., Modlin R. L., Barnes P. F. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest. 1994 Apr;93(4):1733–1739. doi: 10.1172/JCI117157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zhang M., Gong J., Iyer D. V., Jones B. E., Modlin R. L., Barnes P. F. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest. 1994 Dec;94(6):2435–2442. doi: 10.1172/JCI117611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zhang M., Lin Y., Iyer D. V., Gong J., Abrams J. S., Barnes P. F. T-cell cytokine responses in human infection with Mycobacterium tuberculosis. Infect Immun. 1995 Aug;63(8):3231–3234. doi: 10.1128/iai.63.8.3231-3234.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]

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