Background Leflunomide (A 771726) has been shown recently to be effective in rheumatoid arthritis (RA). It inhibits cell proliferation in activated lymphocytes. Its faster onset of action could be due to both antiinflammatory and immunoregulatory properties.
Objectives The present study evaluated the effects of the drug on cytokine production in cultured human rheumatoid synovial cells.
Methods Adherent synovial cells were obtained by collagenase digestion of synovium, isolated from RA patients undergoing surgery. Between passages 4 and 6, cultured synovial cells were incubated with 6 different concentrations of leflunomide (10,20,40,60,80 and 100 μM) and dexamethasone for 24 h. Lipopolysaccharides (LPS) were or were not added for the last 6 h of incubation. Supernatants were assayed for IL-1 receptor antagonist (IL-1 RA), soluble type I receptor of tumour necrosis factor (sTNF RI) and interleukin-6 (IL-6) productions by ELISA. Statistical analysis of differences was carried out by analysis of variance (ANOVA).
Results IL-1 RA and IL-6 production of LPS-stimulated synovial cells were respectively 2.4- and 1.7-fold higher than that of unstimulated cells. LPS did not enhance the production of sTNF RI. Leflunomide increased significantly (p < 0,001) the production of IL-1 RA in a dose dependent manner with a plateau effect beyond 80 μM. Leflunomide decreased significantly (p < 0,001) the IL-6 production by 70 to 75% in a dose dependent manner. On the other hand, leflunomide did not have a significant effect on sTNF RI production. Dexamethasone decreased all the cytokine productions.
Conclusion Leflunomide could have an immunomodulatory action in the cytokine network involved in the pathogenesis of RA with a decrease production of the proinflammatory cytokine IL-6 and increase synthesis of the antiinflammatory cytokine IL-1 RA.
This work has been supported by Aventis Pharma laboratory.
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