Interleukin-6 Induces the Down Regulation of Human Peroxisome Proliferator Activated Receptor Alpha via the MAPK-induced STAT Pathway in Human Hepatocytes
Year: 2013
Type: article
Abstract: IL-6 plays a crucial role in the development of acutephase response. One of the important regulators ofIL-6-activated APR is peroxisome proliferator activatedreceptor alpha (PPARα). Currently, there is a growing interestin determining the role of PPARα in regulating the geneexpression of acute phase proteins. However, studies into themolecular mechanisms and signaling pathways in mediatingthe effects of IL-6 on the expression of PPARα are extremelylimited. In this study, we determined that MAPK pathways, p38and ERK but not JNK were involved in the down regulation ofPPARα by IL-6 via the activation of SHP2. ERK may exert itseffect by activating the downstream transcription factor,C/EBPα and -β. By contrast, ATF2 was not activated by p38suggesting that p38 may produce its effect via othertranscription factors. In this study, we also identified that, p38and ERK pathways were involved in the DNA binding ofSTAT1 and -3, and were responsible for mediating theinhibitory action of STAT1 and -3 on PPARα promoteractivity. Accordingly, this study has unravelled novel pathwaysby which IL-6 inhibits PPARα gene transcription, involving themodulation of p38 and ERK-C/EBP by activating the bindingof STAT1 and -3 to STAT binding site on PPARα promoter.These findings represent a new model of IL-6-inducedsuppression of PPARα expression by the induction of STAT1 and STAT3 phosphorylation and the subsequent down-regulation of PPARα mRNA expression.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2136553975