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TNF- Suppresses IFN--Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class II trans-Activator mRNA¹

Yulong Han^*, Z-H. Lucy Zhou^* and Richard M. Ransohoff^2,*,

^* Department of Neuroscience, The Lerner Research Institute, and Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH 44195

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--induced MHC class II transcription. TNF- is commonly coexpressed with IFN- during immune-mediated inflammatory responses and modulates IFN--stimulated MHC class II expression. The effect of TNF- on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF- suppresses IFN--induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF- also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN- or tetracycline, was destabilized in the presence of TNF-, suggesting that TNF- utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF- blocked IFN--induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF- or IFN-. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.

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