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Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis

Abstract

Tumor necrosis factor-α occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that Interleukin-15 (IL-15) can induce TNF-α production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-α production by macrophages via a cell-contact-dependent mechanism. Freshly isolated RA synovial T cells possessed similar capability, and in vitro, IL-15 was necessary to maintain this activity. IL-15 also induced direct TNF-α production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-α production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1α were ineffective. Antibodies against C069, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.

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References

  1. Burmester, G. et al. The tissue architecture of synovial membrane in inflammatory and non-inflammatory joint diseases. Rheum. Int. 3, 173–180 (1983).

    Article  CAS  Google Scholar 

  2. Miossec, P., Chomarat, P. & Dechanet, J. Bypassing the antigen to control rheumatoid arthritis. Immunol. Today 17, 170–173 (1996).

    Article  CAS  Google Scholar 

  3. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  4. Firestein, G.S. & Zwaifler, N.J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768–773 (1990).

    Article  CAS  Google Scholar 

  5. Simon, K., Seipelt, E. & Sieper, J. Divergent T cell cytokine patterns in inflammatory arthritis. Proc. Natl. Acad. Sci. USA 91, 8562–8566 (1994).

    Article  CAS  Google Scholar 

  6. Ulfgren, A.K., Lindblad, S., Klares Kog, L., Andersson, J. & Andersson, U. Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann. Rheum. Dis. 54, 654–661 (1995).

    Article  CAS  Google Scholar 

  7. Firestein, G. et al. Cytokines in chronic inflammatory arthritis: Failure to detect T cell lymphokines (IL-2 and IL-3) and presence of macrophage colony stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J. Exp. Med. 168, 1573–1586 (1988).

    Article  CAS  Google Scholar 

  8. Panayi, G.S., Lanchbury, J.S. & Kingsley, G.H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 35, 729–735 (1992).

    Article  CAS  Google Scholar 

  9. Staines, N. & Wooley, P.H. Collagen arthritis — what can it teach us? Br. J. Rheum. 33, 798–807 (1994).

    Article  CAS  Google Scholar 

  10. Harrison, W.B., Cyclosporin. in Second-Line Agents in the Treatment of Rheumatic Diseases, (eds. Dixon, J.S. & Furst, D.E.) (Dekker, New York, 1992).

    Google Scholar 

  11. Gregerson, P.K., Silver, J. & Winchester, R.J. The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    Article  Google Scholar 

  12. Mclnnes, I.B. et al. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nature Med. 2, 175–182 (1996).

    Article  Google Scholar 

  13. Grabstein, K.H. et al. Cloning of a T cell growth factor that interacts with the β-chain of the interleukin-2 receptor. Science 264, 965–967 (1994).

    Article  CAS  Google Scholar 

  14. Burton, J.D. et al. A lymphokine, provisionally designated interleukin T and produced by a human adult T cell leukemia line, stimulates T cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl. Acad. Sci. USA 91, 4935–4939 (1994).

    Article  CAS  Google Scholar 

  15. Giri, J.G. et al. Utilization of the b and g chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822–2830 (1994).

    Article  CAS  Google Scholar 

  16. Giri, J.G. et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the a chain of the IL-2 receptor. EMBO J. 14, 3654–3663 (1995).

    Article  CAS  Google Scholar 

  17. Armitage, R.J., MacDuff, B.M., Eisenman, J., Paxton, R. & Grabstein, K.H. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J. Immunol. 154, 483–490 (1995).

    CAS  Google Scholar 

  18. Carson, W.E. et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor, J. Exp. Med. 180, 1395–1403 (1994).

    Article  CAS  Google Scholar 

  19. Akbar, A.N. et al. Interleukin-2 receptor common g-chain signalling 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. 26, 294–299 (1996).

    CAS  Google Scholar 

  20. Wilkinson, P.C. & Liew, F.Y. Chemoattraction of human blood T lymphocytes by IL-15. J. Exp. Med. 181, 1255–1259 (1995).

    Article  CAS  Google Scholar 

  21. AI-Mughales, J., Blyth, T.H., Hunter, J. & Wilkinson, P.C. The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines. Clin. Exp. Immunol. 106, 230–236 (1996).

    Article  Google Scholar 

  22. Arend, W.P., St Dayer, J.-M. Inhibition of the production and effects of interleukin-1 and tumour necrosis factor a in rheumatoid arthritis. Arthritis Rheum. 38, 151–160 (1995).

    Article  CAS  Google Scholar 

  23. Elliot, M.J. et al. Randomised double blind comparison of a chimaeric monoclonal antibody to tumour necrosis factor a (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1995).

    Article  Google Scholar 

  24. Rankin, E.C.C. et al. The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CD571) in rheumatoid arthritis. Br. J Rheum. 34, 334–342 (1995).

    Article  CAS  Google Scholar 

  25. Lacraz, S., Isler, P., Vey, E., Welgus, H.G. & Dayer, J.-M. Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. J. Biol. Chem. 269, 22027–22033 (1994).

    CAS  PubMed  Google Scholar 

  26. Kohem, C.L. et al. Enrichment of differentiated CD45RBdim, CD27-memory T cells in peripheral blood, synovial fluid and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 39, 844–854 (1996).

    Article  CAS  Google Scholar 

  27. Chu, C., Field, M., Feldmann, M. & Maini, R.N. Localisation of tumour necrosis factor alpha in synovial tissue and at the cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).

    Article  CAS  Google Scholar 

  28. Fernandez-Gutierrez, B., Hernandez-Garcia, C., Banares, A.A. & Joier, J.A. Characterisation and regulation of CD69 expression on rheumatoid arthritis synovial fluid T cells. J. Rheumatol. 22, 413–420 (1995).

    CAS  Google Scholar 

  29. Burmester, G. et al. Differential expression of la antigens by rheumatoid synovial lining cells. J. Clin. Invest. 80, 595–604 (1987).

    Article  CAS  Google Scholar 

  30. Laffon, A. et al. Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis. J. Clin. Invest. 88, 546–552 (1991).

    Article  CAS  Google Scholar 

  31. Iannone, F., Corrigall, V.M., Kingsley, G. & Panayi, G. Evidence for continuous recruitment and of T cells into the joints of patients with rheumatoid arthritis. Eur. J. Immunol. 24, 2706–2713 (1994)

    Article  CAS  Google Scholar 

  32. Kanegane, H. & Tosato, G. Activation of naive and memory T cells by interleukin-15. Blood 88, 230–235 (1996).

    CAS  PubMed  Google Scholar 

  33. Struyk, L. et al. T cell receptors in rheumatoid arthritis Arthritis Rheum. 38, 577–589 (1996).

    Article  CAS  Google Scholar 

  34. Nieto, M. Angel del Pozo, M. & Sanchez-Madrid, F. Interleukin-15 induces adhesion molecule redistribution in T lymphocytes, Eur. J. Immunol. 26, 1302–1307 (1996).

    Article  CAS  Google Scholar 

  35. Perrella, O., Carrieri, P.B., De Mercato, R. & Buscaino, G.A. Markers of activated T lymphocytes and T cell receptor gamma/delta+ in patients with multiple sclerosis Eur. Neural. 33, 152–155 (1993).

    Article  CAS  Google Scholar 

  36. Garcia Monzon, C. et al. Expression of a novel activation antigen on intrahepatic CD8+ lymphocytes in viral chronic active hepatitis. Gastroenterology 98, 1029–1035 (1990).

    Article  CAS  Google Scholar 

  37. Testi, R., D'Ambrsoio, D., De Maria, R. & Santoni, A. The CD69 receptor: A multipurpose cell-surface trigger for haematopoietic cells. Immunol. Today 15, 479–483 (1994).

    Article  CAS  Google Scholar 

  38. Isler, P., Vey, E., Zhang, J.-H. & Dayer, J.-M. Cell surface glycoproteins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: A possible role of CD69. fur. Cytokine Netw. 4, 15–23 (1993).

    CAS  Google Scholar 

  39. Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  Google Scholar 

  40. Tagaya, Y., Burton, J.D., Miyamoto, Y. . 8t Waldmann, T.A. Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. EMBOJ. 15, 4928–4939 (1996).

    Article  CAS  Google Scholar 

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McInnes, I., Leung, B., Sturrock, R. et al. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis. Nat Med 3, 189–195 (1997). https://doi.org/10.1038/nm0297-189

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