Interleukin-6 Induces the Down Regulation of Human Peroxisome Proliferator Activated Receptor Alpha via the MAPK-induced STAT Pathway in Human Hepatocytes

IL-6 plays a crucial role in the development of acute phase response. One of the important regulators of IL-6-activated APR is peroxisome proliferator activated receptor alpha (PPARα). Currently, there is a growing interest in determining the role of PPARα in regulating the gene expression of acute phase proteins. However, studies into the molecular mechanisms and signaling pathways in mediating the effects of IL-6 on the expression of PPARα are extremely limited. In this study, we determined that MAPK pathways, p38 and ERK but not JNK were involved in the down regulation of PPARα by IL-6 via the activation of SHP2. ERK may exert its effect by activating the downstream transcription factor, C/EBPα and -β. By contrast, ATF2 was not activated by p38 suggesting that p38 may produce its effect via other transcription factors. In this study, we also identified that, p38 and ERK pathways were involved in the DNA binding of STAT1 and -3, and were responsible for mediating the inhibitory action of STAT1 and -3 on PPARα promoter activity. Accordingly, this study has unravelled novel pathways by which IL-6 inhibits PPARα gene transcription, involving the modulation of p38 and ERK-C/EBP by activating the binding of STAT1 and -3 to STAT binding site on PPARα promoter. These findings represent a new model of IL-6-induced suppression of PPARα expression by the induction of STAT1 and STAT3 phosphorylation and the subsequent down-regulation of PPARα mRNA expression.