title: A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells.
abstract: Chronic inflammation plays a major role in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMC), by expressing and presenting major histocompatibility complex II (MHC II) molecules, help recruit T lymphocyte and initiate the inflammatory response within the vasculature. We have previously shown that VSMCs isolated from mice with deficient adenosine A2b receptor (A2b-null) exhibit higher expression of class II transactivator (CIITA), the master regulator of MHC II transcription, compared to wild type littermates. Here we report that activation of A2b adenosine signaling suppresses CIITA expression in human aortic smooth muscle cells. Down-regulation of CIITA expression was largely attributable to transcriptional repression of type III and IV promoters. Chromatin immunoprecipitation (ChIP) analyses revealed that A2b signaling repressed CIITA transcription by attenuating specific histone modifications on the CIITA promoters in a STAT1-dependent manner. STAT1 interacted with PCAF/GCN5, histone H3K9 acetyltransferases, and WDR5, a key component of the mammalian H3K4 methyltransferase complex, to activate CIITA transcription. A2b signaling prevented recruitment of PCAF/GCN5 and WDR5 to the CIITA promoters in a STAT1-dependent manner. In conclusion, our data suggest that adenosine A2b signaling represses CIITA transcription in VSMCs by manipulating the interaction between STAT1 and the epigenetic machinery.
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China; Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China. Electronic address: hwangnjmu@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China. Electronic address: wpxienjmu@gmail.com.
authors.forename: Weiping
authors.initials: W
authors.lastname: Xie
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China. Electronic address: yjxu2014@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D043705:Receptor, Adenosine A2A; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C083728:MHC class II transactivator protein; C502547:WDR5 protein, human
keywords: Adenosine A2b signaling; CIITA transcription; PCAF/GCN5; STAT1; VSMC; WDR5