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. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209

Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

PMCID: PMC2119001  PMID: 1940799

Abstract

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.

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Selected References

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  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
  3. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bacchetta R., de Waal Malefijt R., Yssel H., Abrams J., de Vries J. E., Spits H., Roncarolo M. G. Host-reactive CD4+ and CD8+ T cell clones isolated from a human chimera produce IL-5, IL-2, IFN-gamma and granulocyte/macrophage-colony-stimulating factor but not IL-4. J Immunol. 1990 Feb 1;144(3):902–908. [PubMed] [Google Scholar]
  5. Baggiolini M., Walz A., Kunkel S. L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 1989 Oct;84(4):1045–1049. doi: 10.1172/JCI114265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  8. De Waal Malefyt R., Alarcon B., Yssel H., Sancho J., Miyajima A., Terhorst C. P., Spits H., De Vries J. E. Introduction of T cell receptor (TCR)-alpha cDNA has differential effects on TCR-gamma delta/CD3 expression by PEER and Lyon-1 cells. J Immunol. 1989 May 15;142(10):3634–3642. [PubMed] [Google Scholar]
  9. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  10. Donnelly R. P., Fenton M. J., Finbloom D. S., Gerrard T. L. Differential regulation of IL-1 production in human monocytes by IFN-gamma and IL-4. J Immunol. 1990 Jul 15;145(2):569–575. [PubMed] [Google Scholar]
  11. Essner R., Rhoades K., McBride W. H., Morton D. L., Economou J. S. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 Jun 1;142(11):3857–3861. [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  13. Figdor C. G., Bont W. S., Touw I., de Roos J., Roosnek E. E., de Vries J. E. Isolation of functionally different human monocytes by counterflow centrifugation elutriation. Blood. 1982 Jul;60(1):46–53. [PubMed] [Google Scholar]
  14. Figdor C. G., Van Es W. L., Leemans J. M., Bont W. S. A centrifugal elutriation system of separating small numbers of cells. J Immunol Methods. 1984 Mar 30;68(1-2):73–87. doi: 10.1016/0022-1759(84)90138-8. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. 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]
  18. Hart P. H., Vitti G. F., Burgess D. R., Whitty G. A., Piccoli D. S., Hamilton J. A. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989 May;86(10):3803–3807. doi: 10.1073/pnas.86.10.3803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Helle M., Brakenhoff J. P., De Groot E. R., Aarden L. A. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol. 1988 Jun;18(6):957–959. doi: 10.1002/eji.1830180619. [DOI] [PubMed] [Google Scholar]
  20. Hsu D. H., de Waal Malefyt R., Fiorentino D. F., Dang M. N., Vieira P., de Vries J., Spits H., Mosmann T. R., Moore K. W. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 1990 Nov 9;250(4982):830–832. doi: 10.1126/science.2173142. [DOI] [PubMed] [Google Scholar]
  21. Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
  22. Koning F., Schreuder I., Giphart M., Bruning H. A mouse monoclonal antibody detecting a DR-related MT2-like specificity: serology and biochemistry. Hum Immunol. 1984 Apr;9(4):221–230. doi: 10.1016/0198-8859(84)90027-2. [DOI] [PubMed] [Google Scholar]
  23. Krug M. S., Berger S. L. First-strand cDNA synthesis primed with oligo(dT). Methods Enzymol. 1987;152:316–325. doi: 10.1016/0076-6879(87)52036-5. [DOI] [PubMed] [Google Scholar]
  24. Lampson L. A., Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed] [Google Scholar]
  25. Lee F., Yokota T., Otsuka T., Gemmell L., Larson N., Luh J., Arai K., Rennick D. Isolation of cDNA for a human granulocyte-macrophage colony-stimulating factor by functional expression in mammalian cells. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4360–4364. doi: 10.1073/pnas.82.13.4360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lonnemann G., Endres S., Van der Meer J. W., Cannon J. G., Koch K. M., Dinarello C. A. Differences in the synthesis and kinetics of release of interleukin 1 alpha, interleukin 1 beta and tumor necrosis factor from human mononuclear cells. Eur J Immunol. 1989 Sep;19(9):1531–1536. doi: 10.1002/eji.1830190903. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. March C. J., Mosley B., Larsen A., Cerretti D. P., Braedt G., Price V., Gillis S., Henney C. S., Kronheim S. R., Grabstein K. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20;315(6021):641–647. doi: 10.1038/315641a0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Nagata S., Tsuchiya M., Asano S., Kaziro Y., Yamazaki T., Yamamoto O., Hirata Y., Kubota N., Oheda M., Nomura H. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. 1986 Jan 30-Feb 5Nature. 319(6052):415–418. doi: 10.1038/319415a0. [DOI] [PubMed] [Google Scholar]
  31. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  32. Schmid J., Weissmann C. Induction of mRNA for a serine protease and a beta-thromboglobulin-like protein in mitogen-stimulated human leukocytes. J Immunol. 1987 Jul 1;139(1):250–256. [PubMed] [Google Scholar]
  33. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  34. Standiford T. J., Strieter R. M., Chensue S. W., Westwick J., Kasahara K., Kunkel S. L. IL-4 inhibits the expression of IL-8 from stimulated human monocytes. J Immunol. 1990 Sep 1;145(5):1435–1439. [PubMed] [Google Scholar]
  35. 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]
  36. Tosato G., Jones K. D. Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. Blood. 1990 Mar 15;75(6):1305–1310. [PubMed] [Google Scholar]
  37. Van Damme J., Cayphas S., Opdenakker G., Billiau A., Van Snick J. Interleukin 1 and poly(rI).poly(rC) induce production of a hybridoma growth factor by human fibroblasts. Eur J Immunol. 1987 Jan;17(1):1–7. doi: 10.1002/eji.1830170102. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Yssel H., De Vries J. E., Koken M., Van Blitterswijk W., Spits H. Serum-free medium for generation and propagation of functional human cytotoxic and helper T cell clones. J Immunol Methods. 1984 Aug 3;72(1):219–227. doi: 10.1016/0022-1759(84)90450-2. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. te Velde A. A., Huijbens R. J., Heije K., de Vries J. E., Figdor C. G. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood. 1990 Oct 1;76(7):1392–1397. [PubMed] [Google Scholar]

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