Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells

Objective. To investigate the potential therapeutic action of the immunomodulatory neuropeptide urocortin (UCN) in an experimental model of rheumatoid arthritis (RA). Methods. After disease onset, DBA/1J mice with collagen-induced arthritis (CIA) were treated with UCN, and the incidence, severity (clinical score), and joint histopathology were evaluated. The inflammatory response was determined by measuring the levels of different mediators of inflammation (cytokines and chemokines) in the joints and sera. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen and by assaying the content of serum autoantibodies. The number of regulatory CD4+,CD25+ T cells and their capacity to suppress self-reactive Th1 cells were determined in joints and lymph nodes. Results. UCN treatment significantly reduced the incidence and severity of CIA, completely abrogating joint swelling and cartilage and bone destruction. The therapeutic effect of UCN was associated with a striking reduction of the 2 deleterious components of the disease: the Th1-driven autoinumme response and the inflammatory response. UCN also induced the generation and/or activation of efficient interleukin-10/ transforming growth factor beta 1-producing Treg cells in arthritis with the capacity to suppress the autoreactive response and to restore immune tolerance, thus playing a pivotal role in the therapeutic effect of UCN. Conclusion. Our findings provide a powerful rationale for assessing the efficacy of UCN as a novel multistep therapeutic approach to the treatment of RA in humans.