Role of PKCdelta in IFN-gamma-inducible CIITA gene expression.
The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCdelta plays an important role in regulating IFN-gamma-inducible CIITA gene expression in macrophages. Inhibition of PKCdelta by either a PKCdelta inhibitor or a dominant negative (DN) mutant form of PKCdelta led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCdelta inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-gamma induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCdelta did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCdelta is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-gamma in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-gamma inducible CIITA promoter, the effect of PKCdelta on CIITA expression is mediated primarily by serine phosphorylation of Stat 1.
Kwon
Myung-Ja
MJ
Department of Microbiology and Immunology, The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Yao
Yongxue
Y
Walter
Michael J
MJ
Holtzman
Michael J
MJ
Chang
Cheong-Hee
CH
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; C085746:rottlerin; D051745:Protein Kinase C-delta