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The mechanism of action of interleukin- 22 (IL-22) in inflammatory arthritis remains unknown. IL-22-deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen-induced arthritis (CIA). Further, administration of anti-IL-22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL-22 in modulating target organ inflammation.CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL-22 and its receptor (IL-22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL-22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme-linked immunosorbent assay (ELISA). Recombinant IL-22 with or without anti-IL-10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA.IL-22 and IL-22R were up-regulated in lymphoid organs and joints during the course of arthritis. IL-22 augmented IL-10, IL-17, and IL-6 in lymphoid tissues in vitro. Administration of recombinant IL-22 was associated with an increase in IL-10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti-IL-10 antibody treatment was associated with the abrogation of this protective effect of IL-22.Our data demonstrate, for the first time, that IL-22 has a protective role in inflammatory arthritis.