The IFN-gamma-induced transcriptional program of the CIITA gene is inhibited by statins.
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that exert anti-inflammatory effects. IFN-gamma induction of class II MHC expression, which requires the class II transactivator (CIITA), is inhibited by statins; however, the molecular basis for suppression is undetermined. We describe that statins inhibit IFN-gamma-induced class II MHC expression by suppressing CIITA gene expression, which is dependent on the HMG-CoA reductase pathway. In addition, CIITA expression is inhibited by GGTI-298 or Clostridium difficile Toxin A, specific inhibitors of Rho family protein prenylation, indicating the involvement of small GTPases. Rac1 is involved in IFN-gamma inducible expression of CIITA, and statins inhibit IFN-gamma-induced Rac1 activation, contributing to the inhibitory effect of statins. IFN-gamma induction of the CIITA gene is regulated by the transcription factors STAT-1alpha, interferon regulatory factor (IRF)-1 and upstream stimulatory factor (USF)-1. We previously reported that statins inhibit constitutive STAT-1alpha expression. IRF-1, a STAT-1 dependent gene, is also inhibited by statins. Therefore, statin treatment results in decreased recruitment of STAT-1alpha and IRF-1 to the endogenous CIITA promoter IV (pIV). The recruitment of USF-1 to CIITA pIV is also reduced by statins, as is the recruitment of RNA polymerase II (Pol II), p300 and Brg-1. These data indicate that statins inhibit the transcriptional program of the CIITA gene.
Lee
Sun J
SJ
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Qin
Hongwei
H
Benveniste
Etty N
EN
D000818:Animals; D005802:Genes, MHC Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors; D050832:Interferon-Stimulated Gene Factor 3 / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D051720:Upstream Stimulatory Factors / Q000037:antagonists & inhibitors; D020830:rac1 GTP-Binding Protein / Q000502:physiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; C079868:gamma interferon activation factor; D007371:Interferon-gamma; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein