Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2-and PI3K-induced STAT1/3 in HepG2 hepatocyte cells

Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPAR alpha). Currently, there is a growing interest in determining the role of PPARa in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPAR alpha are limited. We previously revealed that IL-6 inhibits PPAR alpha gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPAR alpha. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPAR alpha protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPAR alpha mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPAR alpha promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPAR alpha promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPAR alpha protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPAR alpha gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPAR alpha promoter. Together, these findings represent a new model of IL-6-induced suppression of PPAR alpha expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPAR alpha mRNA expression.