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 ORCID: https://orcid.org/0000-0002-6419-5578 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:	19 Oct 2022 08:33
URI:	https://orca.cardiff.ac.uk/id/eprint/18213

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