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

J A G van Roon, K A F M Glaudemans, J W J Bijlsma, F P J G Lafeber

Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands

Correspondence to:
Correspondence to:
Dr J A G van Roon, Department of Rheumatology and Clinical Immunology, (F02.127), University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands;
J.vanRoon{at}digd.azu.nl

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 (TNF), IL1ß, interferon (IFN), and IL4 was measured by enzyme linked immunosorbent assay (ELISA) and by single cell FACS analysis. Expression of the IL7 receptor 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 TNF production by SFMC and very potently stimulated IFN and TNF production by SF CD4+ T cells. These effects were probably mediated through the IL7 receptor 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 TNF mediated proinflammatory responses in patients with RA.

Keywords: interleukin 7; Th1/Th2; tumour necrosis factor ; rheumatoid arthritis; interleukin 12

Abbreviations: CRP, C reactive protein; DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme linked immunosorbent assay; IFN, interferon ; IL, interleukin; MC, mononuclear cells; RA, rheumatoid arthritis; SF, synovial fluid; SFMC, synovial fluid mononuclear cells, TNF, tumour necrosis factor

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