Resistance of rheumatoid synovial dendritic cells to the immunosuppressiveeffects of IL-10

IL-10 down-regulates the APC function of many dendritic cells (DC), includi ng human peripheral blood (PB) DC. In rheumatoid arthritis (RA), synovial f luid (SF) DC express markers of differentiation and are effective APC despi te abundant synovial IL-10. The regulation of DC responsiveness to IL-10 wa s therefore examined by comparing the effect of IL-10 on normal PB and RA S F DC. Whereas IL-10 down-modulated APC function and MHC class II and B7 exp ression of PB DC, IL-10 had no such effect on SF DC. Since SF DC have diffe rentiated in vivo in the presence of proinflammatory cytokines, PB DC were cocultured in the presence of IL-10 and either GM-CSF, IL-1 beta, TNF-alpha , IL-6, or TGF-beta, GM-CSF, IL-1 beta, and TNF-alpha were all able to rest ore APC function. Whereas the effects of IL-10 on PB DC were shown to be me diated by IL-10R1, neither PB nor RA SF DC constitutively expressed IL-10R1 mRNA or detectable surface protein. In contrast, IL-10R1 protein was demon strated in PB and SF DC whole cell lysates, suggestive of predominant intra cellular localization of the receptor. Thus, DC responsiveness to IL-10 may be regulated through modulation of cell surface IL-10R1 expression or sign aling.