title: IFN-gamma regulation of class II transactivator promoter IV in macrophages and microglia: involvement of the suppressors of cytokine signaling-1 protein.
abstract: The discovery of the class II transactivator (CIITA) transcription factor, and its IFN-gamma-activated promoter (promoter IV), have provided new opportunities to understand the molecular mechanisms of IFN-gamma-induced class II MHC expression. Here, we investigated the molecular regulation of IFN-gamma-induced murine CIITA promoter IV activity in microglia/macrophages. In the macrophage cell line RAW264.7, IFN-gamma inducibility of CIITA promoter IV is dependent on an IFN-gamma activation sequence (GAS) element and adjacent E-Box, and an IFN response factor (IRF) element, all within 196 bp of the transcription start site. In both RAW cells and the microglia cell line EOC20, two IFN-gamma-activated transcription factors, STAT-1alpha and IRF-1, bind the GAS and IRF elements, respectively. The E-Box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Functionally, the GAS, E-Box, and IRF elements are each essential for IFN-gamma-induced CIITA promoter IV activity. The effects of the suppressors of cytokine signaling-1 (SOCS-1) protein on IFN-gamma-induced CIITA and class II MHC expression were examined. Ectopic expression of SOCS-1 inhibits IFN-gamma-induced activation of CIITA promoter IV and subsequent class II MHC protein expression. Interestingly, SOCS-1 inhibits the constitutive expression of STAT-1alpha and its IFN-gamma-induced tyrosine phosphorylation and binding to the GAS element in CIITA promoter IV. As well, IFN-gamma-induced expression of IRF-1 and its binding to the IRF element is inhibited. These results indicate that SOCS-1 may be responsible for attenuating IFN-gamma-induced CIITA and class II MHC expression in macrophages.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: O'Keefe
authors.forename: V T
authors.initials: VT
authors.lastname: Nguyen
authors.forename: L L
authors.initials: LL
authors.lastname: Ping Tang
authors.forename: E N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins; D012097:Repressor Proteins; D020218:Response Elements / Q000276:immunology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; C494258:Irf1 protein, mouse; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; D007371:Interferon-gamma