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. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041

Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma- production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells

PMCID: PMC2191152  PMID: 8102388

Abstract

Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN- gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL- 10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma- inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.

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Selected References

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  1. Anegón I., Cuturi M. C., Trinchieri G., Perussia B. Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med. 1988 Feb 1;167(2):452–472. doi: 10.1084/jem.167.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Cassatella M. A., Hartman L., Perussia B., Trinchieri G. Tumor necrosis factor and immune interferon synergistically induce cytochrome b-245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells. J Clin Invest. 1989 May;83(5):1570–1579. doi: 10.1172/JCI114054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan S. H., Perussia B., Gupta J. W., Kobayashi M., Pospísil M., Young H. A., Wolf S. F., Young D., Clark S. C., Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. doi: 10.1084/jem.173.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chehimi J., Starr S. E., Frank I., Rengaraju M., Jackson S. J., Llanes C., Kobayashi M., Perussia B., Young D., Nickbarg E. Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients. J Exp Med. 1992 Mar 1;175(3):789–796. doi: 10.1084/jem.175.3.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cuturi M. C., Murphy M., Costa-Giomi M. P., Weinmann R., Perussia B., Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. doi: 10.1084/jem.165.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Desai B. B., Quinn P. M., Wolitzky A. G., Mongini P. K., Chizzonite R., Gately M. K. IL-12 receptor. II. Distribution and regulation of receptor expression. J Immunol. 1992 May 15;148(10):3125–3132. [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  13. Fontaine S., Damais C., Lando D., Cousin M. A. Monoclonal antibodies to human interleukin-1 beta and their use in a sensitive two-site enzyme linked immunosorbent assay. Lymphokine Res. 1989 Summer;8(2):129–139. [PubMed] [Google Scholar]
  14. Gately M. K., Desai B. B., Wolitzky A. G., Quinn P. M., Dwyer C. M., Podlaski F. J., Familletti P. C., Sinigaglia F., Chizonnite R., Gubler U. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed] [Google Scholar]
  15. Gately M. K., Wolitzky A. G., Quinn P. M., Chizzonite R. Regulation of human cytolytic lymphocyte responses by interleukin-12. Cell Immunol. 1992 Aug;143(1):127–142. doi: 10.1016/0008-8749(92)90011-d. [DOI] [PubMed] [Google Scholar]
  16. Gazzinelli R. T., Oswald I. P., James S. L., Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992 Mar 15;148(6):1792–1796. [PubMed] [Google Scholar]
  17. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  19. Hsu D. H., Moore K. W., Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. doi: 10.1093/intimm/4.5.563. [DOI] [PubMed] [Google Scholar]
  20. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Murphy M., Loudon R., Kobayashi M., Trinchieri G. Gamma interferon and lymphotoxin, released by activated T cells, synergize to inhibit granulocyte/monocyte colony formation. J Exp Med. 1986 Jul 1;164(1):263–279. doi: 10.1084/jem.164.1.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Oswald I. P., Gazzinelli R. T., Sher A., James S. L. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J Immunol. 1992 Jun 1;148(11):3578–3582. [PubMed] [Google Scholar]
  25. Perussia B., Chan S. H., D'Andrea A., Tsuji K., Santoli D., Pospisil M., Young D., Wolf S. F., Trinchieri G. Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta+ T lymphocytes, and NK cells. J Immunol. 1992 Dec 1;149(11):3495–3502. [PubMed] [Google Scholar]
  26. Perussia B., Ramoni C., Anegon I., Cuturi M. C., Faust J., Trinchieri G. Preferential proliferation of natural killer cells among peripheral blood mononuclear cells cocultured with B lymphoblastoid cell lines. Nat Immun Cell Growth Regul. 1987;6(4):171–188. [PubMed] [Google Scholar]
  27. Ralph P., Nakoinz I., Sampson-Johannes A., Fong S., Lowe D., Min H. Y., Lin L. IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor. J Immunol. 1992 Feb 1;148(3):808–814. [PubMed] [Google Scholar]
  28. Sher A., Oswald I. P., Hieny S., Gazzinelli R. T. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha. J Immunol. 1993 May 1;150(9):3982–3989. [PubMed] [Google Scholar]
  29. 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]
  30. Wherry J. C., Schreiber R. D., Unanue E. R. Regulation of gamma interferon production by natural killer cells in scid mice: roles of tumor necrosis factor and bacterial stimuli. Infect Immun. 1991 May;59(5):1709–1715. doi: 10.1128/iai.59.5.1709-1715.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]
  32. 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]

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