Stat2-dependent regulation of MHC class II expression.
MHC type II (MHC II) expression is tightly regulated in macrophages and potently induced by IFN-gamma (type II IFN). In contrast, type I IFNs (IFN-Is), which are far more widely expressed, fail to induce MHC II expression, even though both classes of IFNs direct target gene expression through Stat1. The unexpected finding that IFN-Is effectively induce MHC II expression in Stat2(-/-) macrophages provided an opportunity to explore this conundrum. The ensuing studies revealed that deletion of Stat2, which uniquely transduces signals for IFN-Is, leads to a loss in the IFN-I-dependent induction of suppressor of cytokine signaling-1. Impairment in the expression of this important negative regulator led to a striking prolongation in IFN-I-dependent Stat1 activation, as well as enhanced expression of the target gene, IFN-regulatory factor-1. The prolonged activity of these two transcription factors synergized to drive the transcription of CIITA, the master regulator of MHC II expression, analogous to the pattern observed in IFN-gamma-treated macrophages. Thus, IFN-I-dependent suppressor of cytokine signaling-1 expression plays an important role in distinguishing the biological response between type I and II IFNs in macrophages.
Zhao
Wenli
W
Department of Microbiology, Columbia University, Hammer Health Science Center, 701 West 168th Street, New York, NY 10032, USA.
Cha
Edward N
EN
Lee
Carolyn
C
Park
Christopher Y
CY
Schindler
Christian
C
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007739:L Cells; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000276:immunology; D050795:STAT2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D016898:Interferon-alpha; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D050795:STAT2 Transcription Factor; C491590:Socs1 protein, mouse; C494085:Stat2 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators