Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 38, Issue 8, Pages 2325-2336Publisher
WILEY
DOI: 10.1002/eji.200838189
Keywords
CIITA gene expression; macrophages; small G-proteins; statins
Categories
Funding
- NIH [NS45290, NS50665, NS57563]
- National Multiple Sclerosis Society [PPI129]
- University of Alabama at Birmingham [AM20614]
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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-1 alpha, interferon regulatory factor (IRF)-1 and upstream stimulatory factor (USF)-1. We previously reported that statins inhibit constitutive STAT-1 alpha expression. IRF-1, a STAT-1 dependent gene, is also inhibited by statins. Therefore, statin treatment results in decreased recruitment of STAT-1 alpha 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.
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