TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression.
Recently, a non-DNA binding protein, class II transactivator (CIITA), has been shown to be required for constitutive and IFN-gamma-inducible class II MHC transcription. The cytokine TGF-beta inhibits IFN-gamma-induced class II MHC expression at the transcriptional level. In this study, we provide evidence that TGF-beta blocks IFN-gamma-induced CIITA mRNA accumulation. TGF-beta down-regulates class II MHC and CIITA mRNA accumulation in human astroglioma and fibrosarcoma cell lines, but TGF-beta does not destabilize the CIITA message, suggesting an effect at the transcriptional level. In cells that stably overexpressed CIITA, leading to a constitutive class II MHC-positive phenotype, the inhibitory effect of TGF-beta on class II MHC was abrogated, but the cells remained responsive for expression of TGF-beta-inducible genes. Cell lines that possessed defects in TGF-beta signaling also became refractory to inhibition of IFN-gamma-induced CIITA and class II MHC expression. Our data indicate that TGF-beta suppresses IFN-gamma-induced class II MHC expression by inhibiting accumulation of CIITA mRNA.
Lee
Y J
YJ
Department of Cell Biology, University of Alabama at Birmingham, 35294, USA.
Han
Y
Y
Lu
H T
HT
Nguyen
V
V
Qin
H
H
Howe
P H
PH
Hocevar
B A
BA
Boss
J M
JM
Ransohoff
R M
RM
Benveniste
E N
EN
D001254:Astrocytoma; D005354:Fibrosarcoma; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D018014:Gene Transfer Techniques; D005802:Genes, MHC Class II / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D013752:Tetracycline