Therapeutic effect of a poly(ADP-ribose) polymerase-1 inhibitor on experimental arthritis by downregulating inflammation and Th1 response.
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-aminoisoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleterious 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-specific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-10. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.
Gonzalez-Rey
Elena
E
Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Martínez-Romero
Ruben
R
O'Valle
Francisco
F
Aguilar-Quesada
Rocío
R
Conde
Carmen
C
Delgado
Mario
M
Oliver
F Javier
FJ
D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D001327:Autoimmune Diseases / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007249:Inflammation; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology
C411425:5-aminoisoquinolinone; D016207:Cytokines; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers; D011065:Poly(ADP-ribose) Polymerases