Suppression of tumour necrosis factor production from mononuclear cells by a novel synthetic compound, CLX-090717

Abstract

Objectives. To evaluate the clinical efficacy of a novel synthetic peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, CLX-090717, in several in vitro cell culture systems and murine CIA, an experimental model of RA. Methods. Peripheral blood monocytes purified by elutriation, and rheumatoid synovial cells isolated from clinical tissue were cultured with CLX-090717 and TNF-α release was measured. Molecular mechanism of action was analysed by western blotting and electrophoretic mobility shift assay. Thioglycollate-elicited murine peritoneal macrophages were cultured with CLX-090717 and lipopolysaccharide (LPS)-induced TNF-α release was assayed. Therapeutic studies were done in mice with established arthritis by evaluating clinical parameters and histology. In addition, type II collagen response of lymphocytes from mice with CIA was examined. Results. CLX-090717 significantly inhibited spontaneous TNF-α release by RA synovial membrane cells, as well as LPS-induced TNF-α release from human and murine monocytic cells. Inhibition of TNF-α in monocytes was mediated partially through a nuclear factor-κB (NF-κB)-dependent pathway, as judged by sustained levels of IκBα in cytosolic extracts and a reduced level of LPS-induced NF-κB activity in nuclear extracts. CLX-090717 reduced clinical signs of arthritis and damage to joint architecture when administered therapeutically to arthritic mice. Mechanisms of action in CIA involved the reduction in proliferation of arthritic lymphocytes to antigen in vitro as well as reduced TNF-α release. Conclusions. Our data suggest that the synthetic compound CLX-090717 has potential as a small molecular weight anti-inflammatory therapeutic for chronic inflammatory conditions. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.