High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon FcgammaR triggering.

OBJECTIVE To assess whether DC from RA produce altered cytokine levels and whether this is regulated by triggering of Fc gamma receptors (FcgammaR). METHODS The production of proinflammatory (TNFalpha, IL1, IL6), Th1 (IL12, IFNgamma), and Th2 (IL10) cytokine profiles of immature DC (iDC) from patients with RA and healthy subjects upon triggering of FcgammaR dependent and independent pathways was investigated. iDC, derived from blood monocytes by standardised protocols, were stimulated with immune complexes (IC) at day 6 for 48 hours and, subsequently, for 2 days with LPS in the presence or absence of IC or IFNgamma, resulting in fully matured DC (mDC). IL1, IL6, TNFalpha, IFNgamma, IL12, and IL10 levels in supernatants were measured by ELISA and RIA. RESULTS mDC from patients with RA showed a markedly increased production of IL1, IL6, TNFalpha, and IL10 compared with DC from healthy donors. Triggering of FcgammaR decreased the production of proinflammatory cytokines IL1, IL12, and IFNgamma by iDC and mDC in RA and controls. The production of IL6 and TNFalpha decreased in patients with RA, whereas it was increased in controls. Triggering of FcgammaR independent mechanisms using IFNgamma increased the production of proinflammatory and Th1 cytokines, which was more pronounced in RA. CONCLUSION FcgammaR dependent pathways influence cytokine production by DC. A skewed balance towards proinflammatory and Th1 cytokines in RA can, at least partly, be restored by triggering FcgammaR on DC in RA. Insight into the mechanism which determines the FcgammaR balance might lead to new strategies to abrogate Th1 driven inflammatory processes in RA.