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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Feb 2003; 62(2): 113–119.
PMCID: PMC1754424

Interleukin 7 stimulates tumour necrosis factor α and Th1 cytokine production in joints of patients with rheumatoid arthritis

Abstract

Background: A large number of activated T cells are found in the joints of patients with rheumatoid arthritis (RA). Interleukin 7 (IL7), a T cell growth factor and a regulator of Th1 and Th2 cytokine production, is produced by synoviocytes from patients with RA.

Objective: To investigate the effect on proinflammatory cytokine production of synovial fluid mononuclear cells (SFMC) and the mechanism by which IL7 influences CD4+ T cell activity in patients with RA.

Methods: In a cross sectional group of patients with RA, IL7 levels were compared with those of healthy controls and related to disease activity. The effect of IL7 on cytokine production was tested by RA SFMC and on SF CD4+ T cells in the presence of mononuclear cells (MC). Production of tumour necrosis factor α (TNFα), IL1ß, interferon γ (IFNγ), and IL4 was measured by enzyme linked immunosorbent assay (ELISA) and by single cell FACS analysis. Expression of the IL7 receptor α chain on CD4+ T cells (essential for IL7 signalling) was assessed. Direct effects of IL7 on isolated synovial fluid (SF) CD4+ T cells were studied by cytokine analysis. By neutralisation of IL12 in MC cultures, indirect effects of IL7 on T cells through accessory cells were studied.

Results: IL7 serum levels were higher in patients with RA than in healthy controls and correlated positively with C reactive protein levels. IL7 stimulated TNFα production by SFMC and very potently stimulated IFNγ and TNFα production by SF CD4+ T cells. These effects were probably mediated through the IL7 receptor α chain, which was abundantly expressed on SF CD4+ T cells. Besides the direct stimulation of T cell cytokine production by IL7, its action was partly dependent on IL12, indicating that IL7 also stimulates accessory cell function, leading to T cell activation.

Conclusion: IL7 stimulates proinflammatory cytokine production of intra-articular CD4+ T cells and accessory cells from patients with RA. The correlation with measures of disease activity indicates that IL7 might substantially contribute to the perpetuation of Th1 and TNFα mediated proinflammatory responses in patients with RA.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Albani S, Keystone EC, Nelson JL, Ollier WE, La Cava A, Montemayor AC, Weber DA, Montecucco C, Martini A, Carson DA. Positive selection in autoimmunity: abnormal immune responses to a bacterial dnaJ antigenic determinant in patients with early rheumatoid arthritis. Nat Med. 1995 May;1(5):448–452. [PubMed]
  • Miossec P, Chomarat P, Dechanet J. Bypassing the antigen to control rheumatoid arthritis. Immunol Today. 1996 Apr;17(4):170–173. [PubMed]
  • van Roon JA, Lafeber FP, Bijlsma JW. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum. 2001 Jan;44(1):3–12. [PubMed]
  • Dolhain RJ, van der Heiden AN, ter Haar NT, Breedveld FC, Miltenburg AM. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 1996 Dec;39(12):1961–1969. [PubMed]
  • Morita Y, Yamamura M, Kawashima M, Harada S, Tsuji K, Shibuya K, Maruyama K, Makino H. Flow cytometric single-cell analysis of cytokine production by CD4+ T cells in synovial tissue and peripheral blood from patients with rheumatoid arthritis. Arthritis Rheum. 1998 Sep;41(9):1669–1676. [PubMed]
  • Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. [PMC free article] [PubMed]
  • van Roon JA, Verhoef CM, van Roy JL, Gmelig-Meyling FH, Huber-Bruning O, Lafeber FP, Bijlsma JW. Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease. Ann Rheum Dis. 1997 Nov;56(11):656–660. [PMC free article] [PubMed]
  • Steiner G, Tohidast-Akrad M, Witzmann G, Vesely M, Studnicka-Benke A, Gal A, Kunaver M, Zenz P, Smolen JS. Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) 1999 Mar;38(3):202–213. [PubMed]
  • Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999 May;42(5):963–970. [PubMed]
  • Berner B, Wolf G, Hummel KM, Müller GA, Reuss-Borst MA. Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis. Ann Rheum Dis. 2000 Mar;59(3):190–195. [PMC free article] [PubMed]
  • McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med. 1997 Feb;3(2):189–195. [PubMed]
  • Namekawa T, Wagner UG, Goronzy JJ, Weyand CM. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 1998 Dec;41(12):2108–2116. [PubMed]
  • Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999 Nov;104(10):1393–1401. [PMC free article] [PubMed]
  • Morita Y, Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, Ohmoto Y, Modlin RL, Makino H. Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Arthritis Rheum. 1998 Feb;41(2):306–314. [PubMed]
  • Harada S, Yamamura M, Okamoto H, Morita Y, Kawashima M, Aita T, Makino H. Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1999 Jul;42(7):1508–1516. [PubMed]
  • Appasamy PM. Biological and clinical implications of interleukin-7 and lymphopoiesis. Cytokines Cell Mol Ther. 1999 Mar;5(1):25–39. [PubMed]
  • Plum J, De Smedt M, Leclercq G, Verhasselt B, Vandekerckhove B. Interleukin-7 is a critical growth factor in early human T-cell development. Blood. 1996 Dec 1;88(11):4239–4245. [PubMed]
  • Webb LM, Foxwell BM, Feldmann M. Interleukin-7 activates human naive CD4+ cells and primes for interleukin-4 production. Eur J Immunol. 1997 Mar;27(3):633–640. [PubMed]
  • Borger P, Kauffman HF, Postma DS, Vellenga E. IL-7 differentially modulates the expression of IFN-gamma and IL-4 in activated human T lymphocytes by transcriptional and post-transcriptional mechanisms. J Immunol. 1996 Feb 15;156(4):1333–1338. [PubMed]
  • Londei M, Verhoef A, Hawrylowicz C, Groves J, De Berardinis P, Feldmann M. Interleukin 7 is a growth factor for mature human T cells. Eur J Immunol. 1990 Feb;20(2):425–428. [PubMed]
  • Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10049–10053. [PMC free article] [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Verhoef CM, Van Roon JA, Vianen ME, Glaudemans CA, Lafeber FP, Bijlsma JW. Lymphocyte stimulation by CD3-CD28 enables detection of low T cell interferon-gamma and interleukin-4 production in rheumatoid arthritis. Scand J Immunol. 1999 Oct;50(4):427–432. [PubMed]
  • Verhoef CM, van Roon JA, Vianen ME, Bijlsma JW, Lafeber FP. Interleukin 10 (IL-10), not IL-4 or interferon-gamma production, correlates with progression of joint destruction in rheumatoid arthritis. J Rheumatol. 2001 Sep;28(9):1960–1966. [PubMed]
  • Alderson MR, Tough TW, Ziegler SF, Grabstein KH. Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes. J Exp Med. 1991 Apr 1;173(4):923–930. [PMC free article] [PubMed]
  • Shimaoka Y, Attrep JF, Hirano T, Ishihara K, Suzuki R, Toyosaki T, Ochi T, Lipsky PE. Nurse-like cells from bone marrow and synovium of patients with rheumatoid arthritis promote survival and enhance function of human B cells. J Clin Invest. 1998 Aug 1;102(3):606–618. [PMC free article] [PubMed]
  • De Benedetti F, Massa M, Pignatti P, Kelley M, Faltynek CR, Martini A. Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. J Rheumatol. 1995 Aug;22(8):1581–1585. [PubMed]
  • al-Janadi N, al-Dalaan A, al-Balla S, Raziuddin S. CD4+ T cell inducible immunoregulatory cytokine response in rheumatoid arthritis. J Rheumatol. 1996 May;23(5):809–814. [PubMed]
  • Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996 May 3;85(3):307–310. [PubMed]
  • Hickman CJ, Crim JA, Mostowski HS, Siegel JP. Regulation of human cytotoxic T lymphocyte development by IL-7. J Immunol. 1990 Oct 15;145(8):2415–2420. [PubMed]

Figures and Tables

Figure 1
(A) Serum IL7 levels of patients with RA (n=34) compared with an age and sex matched healthy control group (n=32, HC). Mean (SEM) values are given. Patients with RA showed a significantly higher serum IL7 level than HC (p<0.05). (B) The serum ...
Figure 2
IL7 stimulates TNFα production by RA SFMC. SFMC (1x106/ml) were incubated without or with IL7 (10 ng/ml) for five days. Mean (SEM) values are given (n=4). Asterisks indicate significant difference compared with control culture (*p<0.05). ...
Figure 3
Effect of IL7 on cytokine production by RA synovial T cells. (A) SFMC (1x106/ml) were incubated with or without IL7 (10 ng/ml) for five days, followed by T cell-specific stimulation with CD3/CD28 for 24 hours. Secretion of TNFα, IFNγ, ...
Figure 4Figure 4
Effect of IL7 on cytokine production by synovial T cells. SFMC (1x106/ml) from patients with RA were incubated with or without IL7 (10 ng/ml) for five days, followed by specific T cell stimulation with CD3/CD28 for 24 hours. Cytokine production during ...
Figure 5
(A) Expression of the IL7 receptor α chain (CD127) on isolated synovial CD4+ T cells (black histogram) compared with control staining (open histogram). (B) Isolated CD4+ T cells (5x105/ml) were stimulated with CD3/CD28 in the absence or presence ...
Figure 6
Effect of IL12 neutralising antibodies (aIL12) on IL7-stimulated cytokine production by RA synovial T cells. SFMC (1x106/ml) were incubated without (open bars) or with IL7 (10 ng/ml, black bars) and IL12 neutralising antibodies (5 µg/ml, grey ...

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