Abstract
TGF-beta is a immunoregulatory cytokine that inhibits class II MHC expression in a variety of cell types. Previous studies have shown that the class II MHC transactivator (CIITA), a master regulator that controls class II MHC expression, is targeted by TGF-beta for repression of IFN-gamma-induced class II MHC expression in astrocytes. The mechanism(s) underlying the TGF-beta inhibitory effect is not understood. In this study, we demonstrate that TGF-beta inhibition of CIITA expression occurs at the transcriptional level, and that both constitutive and IFN-gamma-induced human CIITA type IV promoter activity is inhibited by TGF-beta. TGF-beta does not affect the signaling events that mediate IFN-gamma activation of CIITA expression; i.e, TGF-beta does not inhibit IFN-gamma-induced STAT-1alpha phosphorylation and/or DNA binding ability, nor is IFN-gamma induction of IFN regulatory factor affected. The inhibitory effect of TGF-beta on the type IV CIITA promoter is mediated through a promoter region within 80 bp from the transcription start site. Elimination of TGF-beta inhibition of class II MHC and CIITA expression in Smad3-deficient astrocytes, as well as restoration of the inhibitory effect by overexpression of the Smad3 protein, demonstrates that Smad3 is essential in mediating TGF-beta inhibition of CIITA and class II MHC expression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5' Untranslated Regions / physiology
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Adjuvants, Immunologic / physiology
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Animals
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Base Sequence
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Cells, Cultured
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Down-Regulation* / genetics
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Histocompatibility Antigens Class II / biosynthesis*
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Interferon Regulatory Factor-1
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Interferon-Stimulated Gene Factor 3
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Interferon-gamma / physiology
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Nuclear Proteins*
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Phosphoproteins / metabolism
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Promoter Regions, Genetic
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Protein Binding / genetics
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / genetics
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Smad3 Protein
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / biosynthesis*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors / metabolism
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Transcription, Genetic
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Transforming Growth Factor beta / physiology*
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Upstream Stimulatory Factors
Substances
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5' Untranslated Regions
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Adjuvants, Immunologic
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DNA-Binding Proteins
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Histocompatibility Antigens Class II
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Interferon Regulatory Factor-1
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Interferon-Stimulated Gene Factor 3
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Irf1 protein, mouse
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Irf1 protein, rat
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MHC class II transactivator protein
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Nuclear Proteins
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Phosphoproteins
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Smad3 Protein
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Smad3 protein, mouse
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Smad3 protein, rat
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Upstream Stimulatory Factors
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gamma interferon activation factor
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Interferon-gamma