Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blood from rheumatoid arthritis patients

Abstract

Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity. Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-α, IL-23, IL-17A and IL-21 was measured by ELISA. After stimulation with LPS, the interleukin (IL)-17A (p=0.020) and IL-21 (p=0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-α (p=0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p=0.007), while IL-6 production (p=0.005) significantly increased after 6months of therapy. IL-21 significantly correlated with RF (r=0.917, p<0.01) and antimutated citrullinated vimentin antibodies (r=0.770, p<0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p=0.004) were significant predictors of DAS28-ESR at 6months follow-up. Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA.