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.
Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
Na
N
Li
Rebecca C
RC
Salter
Dipak P
DP
Ramji
D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D002087:Butyrates; D006845:Hydrocarbons, Fluorinated; D007371:Interferon-gamma; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D010671:Phenylurea Compounds; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor; D019821:Simvastatin; D013449:Sulfonamides; D045162:Thiazolidinediones; C453899:GW 7647; C494079:STAT1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides