Major histocompatibility class II transactivator expression in smooth muscle cells from A2b adenosine receptor knock-out mice: cross-talk between the adenosine and interferon-gamma signaling.
Atherosclerosis characterized by sustained inflammation and aberrant extracellular matrix alterations. Our previous investigation has defined major histocompatibility class II transactivator (CIITA) as a key factor in mediating these two processes in smooth muscle cells. Here, we demonstrate that CIITA and major histocompatibility class II expression are elevated in interferon-gamma (IFN-gamma)-treated smooth muscle cells from A2b adenosine receptor (A2bAR(-/-)) knock-out mice, as compared with wild type cells. An A2-type adenosine receptor agonist suppresses these effects of IFN-gamma in wild type cells, which can be blocked by an A2bAR-specific antagonist. We further identify that increased cellular cAMP levels are responsible for the down-regulation of CIITA expression and, hence, reduced IFN-gamma response as evidenced by the following data: 1) direct activation of adenylyl cyclase activity is both necessary and sufficient to suppress the IFN-gamma response; 2) inhibition of phosphodiesterase activity attenuates IFN-gamma induced transcription events; and 3) direct treatment with cAMP analog abrogates CIITA activation and IFN-gamma response. Therefore, our data establish possible cross-talk between the adenosine signaling through cAMP and IFN-gamma during regulation of CIITA expression.
Xu
Yong
Y
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Ravid
Katya
K
Smith
Barbara D
BD
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D043704:Receptor, Adenosine A2B; D015534:Trans-Activators; D007371:Interferon-gamma; D003094:Collagen; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000241:Adenosine; D015056:1-Methyl-3-isobutylxanthine