Effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes

This study was performed to investigate whether peroxisome proliterator-act ivated receptor-gamma (PPAR-gamma) exerted an anti-inflammatory effect on r heumatoid synovial cells and inhibited dysregulated proliferation. The expr ession of PPAR-gamma mRNA in cultured human synoviocytes and THP-1 cells wa s analysed by RT-PCR. PPAR-gamma was expressed in normal, osteoarthritis (O A), rheumatoid arthritis (RA) synovial cells as well as a human monocytic c ell line, THP-1. In RA and OA synoviocytes, the induction of inflammatory c ytokine mRNA expression such as TNF-a and IL-1 beta was significantly inhib ited by the natural PPAR-gamma agonist 15 deoxy-Delta (12,14) prostaglandin J(2), (15d-PGJ,). The effect of PPAR-y on the nuclear factor (NF)-KB activ ity was tested by electrophoretic mobility shift assay (EMSA). Both troglit azone and 15d-PGJ(2) markedly inhibited TNF-a-induced NF-KB activation at 3 0 muM. However, PPAR-y agonist neither reduced proliferation nor induced ap optosis in RA synoviocytes when measured by XTT assay and fluorescence acti vated cell sorter (FACS) analysis. In contrast, it induced apoptosis in a d ose-dependent manner in THP-1 cells and augmented INF-related apoptosis-ind ucing ligand (TRAIL)-induced apoptosis as well. In conclusion, these data d emonstrate that PPAR-gamma is expressed in human synoviocytes and THP-1 cel ls, and the PPAR-7 activation inhibits expression of inflammatory cytokines in RA synoviocytes. Furthermore, PPAR-y activation induces apoptosis by it self and augments TRAIL/ Apo2L-induced apoptosis in THP-1 cells. These resu lts suggest that PPAR-7 agonists may provide a new therapeutic approach for RA. (C) 2001 Academic Press.