TNF-alpha suppresses IFN-gamma-induced MHC class II expression in HT1080 cells by destabilizing class II trans-activator mRNA.
Precise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-gamma-induced MHC class II transcription. TNF-alpha is commonly coexpressed with IFN-gamma during immune-mediated inflammatory responses and modulates IFN-gamma-stimulated MHC class II expression. The effect of TNF-alpha on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-alpha suppresses IFN-gamma-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-alpha also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-gamma or tetracycline, was destabilized in the presence of TNF-alpha, suggesting that TNF-alpha utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-alpha blocked IFN-gamma-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-beta or IFN-beta. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.
Department of Neuroscience, The Lerner Research Institute, Cleveland, OH 44195, USA.
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Han
Z H
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Zhou
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RM
Ransohoff
D005354:Fibrosarcoma; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009154:Mutation / Q000276:immunology; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C034811:tetracycline resistance-encoding transposon repressor protein; D007371:Interferon-gamma; D013752:Tetracycline