PMID- 24242046 OWN - NLM STAT- MEDLINE DCOM- 20141021 LR - 20211203 IS - 1573-4919 (Electronic) IS - 0300-8177 (Linking) VI - 388 IP - 1-2 DP - 2014 Mar TI - Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells. PG - 25-37 LID - 10.1007/s11010-013-1896-z [doi] AB - 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 (PPARalpha). Currently, there is a growing interest in determining the role of PPARalpha in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPARalpha are limited. We previously revealed that IL-6 inhibits PPARalpha 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 PPARalpha. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPARalpha protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPARalpha mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPARalpha promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPARalpha 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 PPARalpha protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPARalpha 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 PPARalpha promoter. Together, these findings represent a new model of IL-6-induced suppression of PPARalpha expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPARalpha mRNA expression. FAU - Chew, Guat-Siew AU - Chew GS AD - School of Biological Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia, h.chew@ballarat.edu.au. FAU - Myers, Stephen AU - Myers S FAU - Shu-Chien, Alexander Chong AU - Shu-Chien AC FAU - Muhammad, Tengku Sifzizul Tengku AU - Muhammad TS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131116 PL - Netherlands TA - Mol Cell Biochem JT - Molecular and cellular biochemistry JID - 0364456 RN - 0 (Androstadienes) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (PPAR alpha) RN - 0 (RNA, Messenger) RN - 0 (STAT1 Transcription Factor) RN - 0 (STAT1 protein, human) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - 0 (Tyrphostins) RN - 0 (alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.2 (JAK2 protein, human) RN - EC 2.7.10.2 (Janus Kinase 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - XVA4O219QW (Wortmannin) SB - IM MH - Acute-Phase Reaction/genetics MH - Androstadienes/pharmacology MH - Binding Sites/genetics MH - Cell Line, Tumor MH - Hep G2 Cells MH - Hepatocytes/*pathology MH - Humans MH - Interleukin-6/biosynthesis/*pharmacology MH - Janus Kinase 2/antagonists & inhibitors/metabolism MH - PPAR alpha/biosynthesis/*genetics MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Promoter Regions, Genetic MH - Protein Binding/genetics MH - RNA, Messenger/biosynthesis MH - STAT1 Transcription Factor/biosynthesis/*metabolism MH - STAT3 Transcription Factor/biosynthesis/*metabolism MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Transcription, Genetic MH - Tyrphostins/pharmacology MH - Wortmannin EDAT- 2013/11/19 06:00 MHDA- 2014/10/22 06:00 CRDT- 2013/11/19 06:00 PHST- 2013/09/06 00:00 [received] PHST- 2013/11/05 00:00 [accepted] PHST- 2013/11/19 06:00 [entrez] PHST- 2013/11/19 06:00 [pubmed] PHST- 2014/10/22 06:00 [medline] AID - 10.1007/s11010-013-1896-z [doi] PST - ppublish SO - Mol Cell Biochem. 2014 Mar;388(1-2):25-37. doi: 10.1007/s11010-013-1896-z. Epub 2013 Nov 16.