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

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. J. Cell. Biochem. 112: 675–683, 2011.