PPAR Agonist, Pioglitazone Inhibits Interleukin-18 (IL-18)-induced Gene Expression and Apoptosis in Cardiac Myocytes

Abstract

Interleukin-18 (IL-18) is a proinflammatory cytokine with multiple functions. We and others have reported that increased levels of circulating IL-18 are thought to be one of risk factors for heart failure. Nuclear factor kappa-B (NF-kB) enhances expression of several cytokines in heart failure. We have demonstrated that IL-18 induced c-fos SRE (Serum Response Element), NF-kB activities and apoptosis through translocation of Rho-kinase (Rho-K) into nucleus in cardiac myocytes. Pioglitazone, a PPAR (peroxisome proliferators-activated receptor) agonist has shown anti-inflammatory activities. In this study, we examined the role of Pioglitazone on IL-18-induced gene expression and apoptosis in cardiac myocytes. Pioglitazone inhibited IL-18-induced and RhoA- or Rho-K-induced c-fos SRE and NF-kB activities. Pioglytazone inhibited IL-18-induced Rho-K-fused-GFP (Green Fluorescence Protein) (GFP-Rho-K) translocation into nucleus. However, Pioglitazone did not inhibit RhoA-mediated Rho-K-GFP translocation into nucleus. From these results, Pioglitazone thought to inhibit at least two different sites from IL-18 receptor to SRE and NF-kB. One site is downstream of Rho-K and the other is upstream of RhoA. Meanwhile, IL-18 induced apoptosis. Pioglitazone also inhibited IL-18-induced apoptosis. PPAR might be one of important molecular targets for IL-18-induced cardiovascular events. Inhibition of IL-18-induced translocation of Rho-K into nucleus by Pioglitazone might be one of novel mechanisms for pleiotropic effects of PPAR.