Molecular Mechanism Of Acute Phase Response: Identification Of Signal Transduction Pathways Mediating Cytokine Inhibitory Effect On Human Peroxisome Proliferator Activated Receptor Alpha (Pparα) In Liver Cells

dc.contributor.author	Chew, Guat Siew
dc.date.accessioned	2018-08-02T07:14:12Z
dc.date.available	2018-08-02T07:14:12Z
dc.date.issued	2010-09
dc.description.abstract	Cytokines, like IL-6, play an important role in triggering the acute phase response (APR) of the body to injury and inflammation. The dynamics of expression and interaction of the IL-6 signalling pathway components in the regulation of peroxisome proliferator-activated receptor alpha (PPARα) during APR remain to be properly identified. In this study, we determined that three possible potential signaling pathways, JAK-STAT, PI3K and MAPK (p38 and ERK1/2) which derived from the upstream JAK and SHP2 components of the IL-6 signalling were involved in IL-6-inhibitory effect on PPARα gene expression. Pre-treatment of cells with the pharmacological inhibitors of JAK2, PI3K and MAPK, demonstrated that IL-6 inhibited the mRNA levels of PPARα via activating the binding of STAT1 and STAT3 to STAT binding site in the PPARα promoter. Moreover, over expression of the STAT1 and STAT3 in the liver cells decreased PPARα promoter activity, indicating that an increase in DNA binding activity of STAT1 and STAT3 inhibited the PPARα gene expression. It was also found that AG490, Rapamycin, SB203580 and U0126 inhibitors attenuated the action of IL-6 on the DNA binding of STAT1 and STAT3, suggesting a cross-talk between the signaling pathways. In short, in the presence of all the inhibitors, the effect of IL-6 on protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited. Taken together, this study has successfully unraveled novel pathways by which IL-6 inhibited PPARα gene transcription, involving the modulation of JAK-STAT, JAK-associated PI3K-Akt-mTOR-STAT and SHP-mediated MAPK (p38-STAT and ERK1/2-STAT) pathways. The present study also underlines the significance of JAK-STAT as a dominant pathway due to cross-talks between JAK-STAT with PI3K, and, MAPK pathways via SHP activation, and, STAT transcription factors in down regulating the PPARα mRNA expression. Thus, the determination of the regulatory pathways of PPARα in IL-6-treated liver cells strongly suggests the potential physiological role for PPARα in modulating APR and may have immediate therapeutic implications in the development of APR.	en_US
dc.identifier.uri	http://hdl.handle.net/123456789/6136
dc.language.iso	en	en_US
dc.publisher	Universiti Sains Malaysia	en_US
dc.subject	Cytokines, like IL-6 triggering the acute phase response	en_US
dc.subject	of the body to injury and inflammation	en_US
dc.title	Molecular Mechanism Of Acute Phase Response: Identification Of Signal Transduction Pathways Mediating Cytokine Inhibitory Effect On Human Peroxisome Proliferator Activated Receptor Alpha (Pparα) In Liver Cells	en_US
dc.type	Thesis	en_US