PPARsと免疫・炎症システム―関節疾患治療への応用―

抄録

Peroxisome proliferator-activated receptors (PPARs), are members of the nuclear hormone receptors superfamily of ligand-activated transcriptional factors that include receptors for steroids, thyroid hormone, vitamin D₃ and retinoic acid. PPAR binds to peroxisome proliferator responsive element (PPRE) as a heterodimer with the retinoic receptor (RXR) in the regulation of PPAR target genes. PPARs have been suggested to be important immunomodulatory factors as well as fatty acid regulators. PPARs modulate these activities in different immune cell types such as monocyte/macrophages, lymphocytes, and endothelial cells. PPAR-γ ligands lead to inhibition of the expression of nitric oxide, cytokines, chemokines and adhesion molecules, in part by antagonizing the activities of the transcription factors such as AP-1, and NF-κB. Moreover PPAR-γ ligands including antidiabetic thiazolidinedione and 15-deoxy-Δ^12,14-prostaglandin J₂ have potent tumor modulatory effects against several cancers. PPAR-γ also expressed in chondrocytes, synovial and bone tissues. Activation of the PPAR-γ induced RA synoviocyte apoptosis and suppression of osteoclast differentiatoin in vitro, and ameliorated adjuvant- induced arthritis with suppression of pannus formation and mononuclear cell infiltration in rats. These findings suggest that PPAR-γ ligands may potentially be useful for the treatment of chronic inflammatory diseases including arthritic joint diseases.