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Molecular mechanisms underlying the inhibition of IFN-γ-induced, STAT1-mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs

Li, Na, Salter, Rebecca Claire and Ramji, Dipak Purshottam 2011. Molecular mechanisms underlying the inhibition of IFN-γ-induced, STAT1-mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs. Journal of Cellular Biochemistry 112 (2) , pp. 675-683. 10.1002/jcb.22976

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Abstract

PPARs and LXRs are ligand-activated transcription factors that are emerging as promising therapeutic targets for limiting atherosclerosis, an inflammatory disorder orchestrated by cytokines. The potent anti-atherogenic actions of these nuclear receptors involve the regulation of glucose and lipid metabolism along with attenuation of the inflammatory response. Similarly, cholesterol-lowering drugs, statins, inhibit inflammation. Unfortunately, the mechanisms underlying such inhibitory actions of these agents in human macrophages are poorly understood and were therefore investigated in relation to IFN-γ, a key pro-atherogenic cytokine, which mediates its cellular effects mainly through STAT1. Simvastatin and PPAR agonists had no effect on the IFN-γ-induced, phosphorylation-mediated activation of STAT1 and its DNA binding but attenuated its ability to activate gene transcription. On the other hand, LXR activators attenuated both DNA binding and trans-activation potential of STAT1 induced by IFN-γ. These studies reveal differences in the mechanism of action of agonists of PPARs (and simvastatin) and LXRs on the IFN-γ-induced, STAT1-mediated gene transcription in human macrophages.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history
Uncontrolled Keywords: IFN-γ; macrophages; STAT1; PPAR; LXR; transcriptional inhibition; simvastatin
Additional Information: Article first published online: 25 JAN 2011
Publisher: John Wiley & Sons
ISSN: 0730-2312
Last Modified: 04 Jun 2017 03:13
URI: http://orca.cf.ac.uk/id/eprint/18213

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