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. 1994 May 1;179(5):1517–1527. doi: 10.1084/jem.179.5.1517

Immunoregulatory role of interleukin 10 in rheumatoid arthritis

PMCID: PMC2191503  PMID: 8163935

Abstract

The presence and the role of interleukin 10 (IL-10), a potent cytokine synthesis inhibitory factor and antiinflammatory cytokine, were investigated in rheumatoid arthritis (RA). The expression of both mRNA and protein for IL-10 could be demonstrated in RA and osteoarthritis (OA) joints. Human IL-10 mRNA could be demonstrated by polymerase chain reaction amplification of cDNA made by reverse transcription of total RNA extracted directly from synovial tissue in five out of five RA and four out of five OA patients. IL-10 protein was demonstrated by specific immunoassay and immunohistology. IL-10 protein was spontaneously produced in all 11 RA and 17 OA synovial membrane cultures investigated, and this production was sustained for up to 5 d in culture in the absence of any extrinsic stimulation. IL-10 protein could also be detected by immunohistology in all five RA and four OA synovial membrane biopsies investigated, but not three normal synovial membranes. Immunohistology revealed that the IL-10 was localized to the synovial membrane lining layer and mononuclear cell aggregates. Immunofluorescence double staining revealed that the sources of IL-10 were monocytes in the lining layer, and T cells in the mononuclear cell aggregates. We found evidence that the IL-10 expression was functionally relevant, as neutralization of endogenously produced IL-10 in the RA synovial membrane cultures resulted in a two- to threefold increase in the protein levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and IL-1 beta, although IL-6 and IL-8 levels were not affected. The addition of exogenous recombinant IL-10 to the RA synovial membrane cultures resulted in a two- to threefold decrease in the levels of TNF-alpha and IL-1 beta. IL-8 levels were reduced by day 5; however, IL-6 levels were not affected by exogenous IL-10. Neutralization of the endogenous IL-10 in two out of seven RA synovial membrane cultures resulted in the expression of detectable levels of interferon gamma (561-1,050 pg/ml). Taken together, the above findings suggest that IL-10 is spontaneously produced in RA and OA and is an important immunoregulatory component in the cytokine network of RA, regulating monocyte and in some cases T cell cytokine production.

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Selected References

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  1. Alvaro-Gracia J. M., Zvaifler N. J., Brown C. B., Kaushansky K., Firestein G. S. Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J Immunol. 1991 May 15;146(10):3365–3371. [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Brennan F. M., Chantry D., Jackson A., Maini R., Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989 Jul 29;2(8657):244–247. doi: 10.1016/s0140-6736(89)90430-3. [DOI] [PubMed] [Google Scholar]
  4. Brennan F. M., Chantry D., Turner M., Foxwell B., Maini R., Feldmann M. Detection of transforming growth factor-beta in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures. Clin Exp Immunol. 1990 Aug;81(2):278–285. doi: 10.1111/j.1365-2249.1990.tb03331.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buchan G., Barrett K., Fujita T., Taniguchi T., Maini R., Feldmann M. Detection of activated T cell products in the rheumatoid joint using cDNA probes to Interleukin-2 (IL-2) IL-2 receptor and IFN-gamma. Clin Exp Immunol. 1988 Feb;71(2):295–301. [PMC free article] [PubMed] [Google Scholar]
  6. Chantry D., Turner M., Abney E., Feldmann M. Modulation of cytokine production by transforming growth factor-beta. J Immunol. 1989 Jun 15;142(12):4295–4300. [PubMed] [Google Scholar]
  7. Chomarat P., Rissoan M. C., Banchereau J., Miossec P. Interferon gamma inhibits interleukin 10 production by monocytes. J Exp Med. 1993 Feb 1;177(2):523–527. doi: 10.1084/jem.177.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Chu C. Q., Field M., Feldmann M., Maini R. N. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1125–1132. doi: 10.1002/art.1780340908. [DOI] [PubMed] [Google Scholar]
  10. Cope A. P., Aderka D., Doherty M., Engelmann H., Gibbons D., Jones A. C., Brennan F. M., Maini R. N., Wallach D., Feldmann M. Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum. 1992 Oct;35(10):1160–1169. doi: 10.1002/art.1780351008. [DOI] [PubMed] [Google Scholar]
  11. Cope A. P., Gibbons D. L., Aderka D., Foxwell B. M., Wallach D., Maini R. N., Feldmann M., Brennan F. M. Differential regulation of tumour necrosis factor receptors (TNF-R) by IL-4; upregulation of P55 and P75 TNF-R on synovial joint mononuclear cells. Cytokine. 1993 May;5(3):205–212. doi: 10.1016/1043-4666(93)90006-q. [DOI] [PubMed] [Google Scholar]
  12. Cush J. J., Lipsky P. E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. doi: 10.1002/art.1780311003. [DOI] [PubMed] [Google Scholar]
  13. Del Prete G., De Carli M., Almerigogna F., Giudizi M. G., Biagiotti R., Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993 Jan 15;150(2):353–360. [PubMed] [Google Scholar]
  14. Deleuran B. W., Chu C. Q., Field M., Brennan F. M., Katsikis P., Feldmann M., Maini R. N. Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis. Br J Rheumatol. 1992 Dec;31(12):801–809. doi: 10.1093/rheumatology/31.12.801. [DOI] [PubMed] [Google Scholar]
  15. Di Giovine F. S., Nuki G., Duff G. W. Tumour necrosis factor in synovial exudates. Ann Rheum Dis. 1988 Sep;47(9):768–772. doi: 10.1136/ard.47.9.768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Eastgate J. A., Symons J. A., Wood N. C., Grinlinton F. M., di Giovine F. S., Duff G. W. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988 Sep 24;2(8613):706–709. doi: 10.1016/s0140-6736(88)90185-7. [DOI] [PubMed] [Google Scholar]
  17. Elliott M. J., Maini R. N., Feldmann M., Long-Fox A., Charles P., Katsikis P., Brennan F. M., Walker J., Bijl H., Ghrayeb J. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993 Dec;36(12):1681–1690. doi: 10.1002/art.1780361206. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Fava R. A., Olsen N. J., Postlethwaite A. E., Broadley K. N., Davidson J. M., Nanney L. B., Lucas C., Townes A. S. Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia. J Exp Med. 1991 May 1;173(5):1121–1132. doi: 10.1084/jem.173.5.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Firestein G. S., Berger A. E., Tracey D. E., Chosay J. G., Chapman D. L., Paine M. M., Yu C., Zvaifler N. J. IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol. 1992 Aug 1;149(3):1054–1062. [PubMed] [Google Scholar]
  21. Firestein G. S., Xu W. D., Townsend K., Broide D., Alvaro-Gracia J., Glasebrook A., Zvaifler N. J. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988 Nov 1;168(5):1573–1586. doi: 10.1084/jem.168.5.1573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Firestein G. S., Zvaifler N. J. Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. II. Low levels of synovial fluid and synovial tissue interferon suggest that gamma-interferon is not the primary macrophage activating factor. Arthritis Rheum. 1987 Aug;30(8):864–871. doi: 10.1002/art.1780300804. [DOI] [PubMed] [Google Scholar]
  23. Guerne P. A., Zuraw B. L., Vaughan J. H., Carson D. A., Lotz M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest. 1989 Feb;83(2):585–592. doi: 10.1172/JCI113921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gérard C., Bruyns C., Marchant A., Abramowicz D., Vandenabeele P., Delvaux A., Fiers W., Goldman M., Velu T. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med. 1993 Feb 1;177(2):547–550. doi: 10.1084/jem.177.2.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Haworth C., Brennan F. M., Chantry D., Turner M., Maini R. N., Feldmann M. Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur J Immunol. 1991 Oct;21(10):2575–2579. doi: 10.1002/eji.1830211039. [DOI] [PubMed] [Google Scholar]
  28. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  29. Hovdenes J., Gaudernack G., Kvien T. K., Egeland T. Expression of activation markers on CD4+ and CD8+ cells from synovial fluid, synovial tissue, and peripheral blood of patients with inflammatory arthritides. Scand J Immunol. 1989 Jun;29(6):631–639. doi: 10.1111/j.1365-3083.1989.tb01167.x. [DOI] [PubMed] [Google Scholar]
  30. Kaczmarek L., Calabretta B., Baserga R. Expression of cell-cycle-dependent genes in phytohemagglutinin-stimulated human lymphocytes. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5375–5379. doi: 10.1073/pnas.82.16.5375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kuruvilla A. P., Shah R., Hochwald G. M., Liggitt H. D., Palladino M. A., Thorbecke G. J. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918–2921. doi: 10.1073/pnas.88.7.2918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lotz M., Kekow J., Carson D. A. Transforming growth factor-beta and cellular immune responses in synovial fluids. J Immunol. 1990 Jun 1;144(11):4189–4194. [PubMed] [Google Scholar]
  33. Lotz M., Tsoukas C. D., Robinson C. A., Dinarello C. A., Carson D. A., Vaughan J. H. Basis for defective responses of rheumatoid arthritis synovial fluid lymphocytes to anti-CD3 (T3) antibodies. J Clin Invest. 1986 Sep;78(3):713–721. doi: 10.1172/JCI112631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Macatonia S. E., Doherty T. M., Knight S. C., O'Garra A. Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production. J Immunol. 1993 May 1;150(9):3755–3765. [PubMed] [Google Scholar]
  35. Miltenburg A. M., van Laar J. M., de Kuiper R., Daha M. R., Breedveld F. C. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol. 1992 May;35(5):603–610. doi: 10.1111/j.1365-3083.1992.tb03260.x. [DOI] [PubMed] [Google Scholar]
  36. Miossec P., Briolay J., Dechanet J., Wijdenes J., Martinez-Valdez H., Banchereau J. Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992 Aug;35(8):874–883. doi: 10.1002/art.1780350805. [DOI] [PubMed] [Google Scholar]
  37. Miyasaka N., Sato K., Goto M., Sasano M., Natsuyama M., Inoue K., Nishioka K. Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction. Arthritis Rheum. 1988 Apr;31(4):480–486. doi: 10.1002/art.1780310404. [DOI] [PubMed] [Google Scholar]
  38. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  39. Saxne T., Palladino M. A., Jr, Heinegård D., Talal N., Wollheim F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. doi: 10.1002/art.1780310816. [DOI] [PubMed] [Google Scholar]
  40. Schröder J. M., Sticherling M., Henneicke H. H., Preissner W. C., Christophers E. IL-1 alpha or tumor necrosis factor-alpha stimulate release of three NAP-1/IL-8-related neutrophil chemotactic proteins in human dermal fibroblasts. J Immunol. 1990 Mar 15;144(6):2223–2232. [PubMed] [Google Scholar]
  41. Silverman H. A., Johnson J. S., Vaughan J. H., McGlamory J. C. Altered lymphocyte reactivity in rheumatoid arthritis. Arthritis Rheum. 1976 May-Jun;19(3):509–515. doi: 10.1002/art.1780190301. [DOI] [PubMed] [Google Scholar]
  42. Street N. E., Mosmann T. R. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. doi: 10.1096/fasebj.5.2.1825981. [DOI] [PubMed] [Google Scholar]
  43. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. Yssel H., De Waal Malefyt R., Roncarolo M. G., Abrams J. S., Lahesmaa R., Spits H., de Vries J. E. IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J Immunol. 1992 Oct 1;149(7):2378–2384. [PubMed] [Google Scholar]
  49. 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]
  50. 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]
  51. 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]
  52. 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]

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