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

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.