PBS-1086, a Rel Inhibitor of NF-κB, Ameliorates Collagen-Induced Arthritis in Mice

Abstract

The family of nuclear factor-kappaB (NF-κB) transcription factors is intimately involved in the regulation of expression of numerous genes in the setting of the inflammatory response. Inflammation, cartilage degradation, cell proliferation, angiogenesis and pannus formation are hallmarks of the pathogenesis of both collagen-induced arthritis (CIA) in rodents and rheumatoid arthritis (RA) in humans. The aim of this study is to investigate the effect of PBS-1086, a ReI inhibitor of NF-κB, on the modulation of the inflammatory response in mice subjected to CIA in comparison to the effect of etanercept. CIA was induced in mice by an intradermal injection of bovine type II collagen (CII) emulsion and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice developed erosive hind paw arthritis when immunised with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri-articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 28 in the CII challenged mice and the severity of CIA progressed over a 35-day period with a resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with PBS-1086 starting at the onset of arthritis (day 21) ameliorated the clinical signs at days 21–35 and improved histological status in the joint and paw. In addition, it also reduced the neutrophil infiltration which is a key mediator of RA. In this study, we demonstrate that PBS-1086 exerts an anti-inflammatory effect during chronic inflammation and ameliorates the tissue damage associated with CIA. The anti-inflammatory activities of PBS-1086 are comparable to those of etanercept treatment.