The Smad3 protein is involved in TGF-beta inhibition of class II transactivator and class II MHC expression.
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.
Dong
Y
Y
Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA.
Tang
L
L
Letterio
J J
JJ
Benveniste
E N
EN
D020121:5' Untranslated Regions / Q000502:physiology; D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051720:Upstream Stimulatory Factors
D020121:5' Untranslated Regions; D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; C494258:Irf1 protein, mouse; C494259:Irf1 protein, rat; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051720:Upstream Stimulatory Factors; C079868:gamma interferon activation factor; D007371:Interferon-gamma