Therapeutic effect of a poly(ADP-ribose) polymerase-1 inhibitor on experimental arthritis by downregulating inflammation and Th1 response

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. Here, we investigate the impact of a selective PARP-1 inhibitor in experimental arthritis. PARP-1 inhibition with 5-aminolsoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and desquction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleteribus components of the disease, i.e. the Th1-driven autoimmune and inflammatory responses. AIQ downregulates the production of various inflammatory cytokines, and chemokines, decreases the antigen-spocific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-110. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein at a potential target for the treatment of rheumatoid arthritis. © 2007 González-Rey et al.