15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

Abstract

IntroductionRheumatoid arthritis (RA) is a chronic, destructive inflammatory polyarticular joint disease, characterized by massive synovial proliferation and subintimal infiltration of inflammatory cells, along with angiogenesis (1, 2).The inflammation of RA results in the production of prostaglandins (PGs) E 2 , cytokines, and nitric oxide (1, 3).In particular, macrophage-derived cytokines such as TNF-α (4) and IL-1 (5), which are abundant in synovial tissues and fluid from patients with RA, are mitogens for synovial fibroblasts, as well as osteoclasts.Blocking of these cytokines inhibits the release of synovial production of other proinflammatory cytokines.This suggests that TNF-α and IL-1 are key proinflammatory molecules in cytokine cascade in RA.In fact, TNF-α receptor antagonists, neutralizing antibodies against TNF-α, and IL-1 receptor antagonist can control joint inflammation in most RA patients (6-8).Moreover, the formation of active inflamed pannus is thought to be critical for erosive disease and results in irreversible destruction of the cartilage and bone in affected joints.The mechanism responsible for synovial hyperplasia leading to pannus formation may be due to reduced apoptosis of inflam-matory cells and tumor-like synoviocytes (9, 10).Therefore, suppression of the production of inflammatory molecules and formation of hyperplastic synovium may be important targets of therapy for RA.Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcriptional factors that include receptors for steroids, thyroid hormone, vitamin D, and retinoic acid (11).PPAR binds to peroxisome proliferator responsive element (PPRE) as a heterodimer with the retinoic receptor (RXR), implying a role of 9-cis retinoic acid in the regulation of PPAR target genes (12, 13).To date, three mammalian PPAR subtypes have been isolated and termed PPAR-α, NUC1 (also known as PPAR-δ), and PPAR-γ (11, 14, 15).PPAR-α is highly expressed in the liver, heart, kidney, muscle, brown adipose tissue, and gut, which exhibit high carbolic rates of fatty acids (14, 16).PPAR-δ may be expressed ubiquitously, and its function is relatively unknown (17).Recent studies suggest that PPAR-δ may be a target for nonsteroidal anti-inflammatory drug-induced (NSAIDinduced) tumor suppression in colorectal tumors (18).PPAR-γ is expressed at high levels in adipose tissue and is a critical regulator of adipocyte differentiation (19).