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 INF-gamma-inducible class II MHC transcription. The cytokine TGF-beta inhibits INF-gamma- induced class II MHC expression at the transcriptional level. In this study, we provide evidence that TGF-beta blocks INF-gamma-induced CIIT A mRNA accumulation. TGF-beta down-regulates class II MHC and CIITA mR NA 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 inhib itory effect of TGF-beta on class II MHC was abrogated, but the cells remained responsive for expression of TGF-beta-inducible genes. Cell l ines that possessed defects in TGF-beta signaling also became refracto ry to inhibition of INF-gamma-induced CIITA and class II MHC expressio n, Our data indicate that TGF-beta suppresses INF-gamma-induced class II MHC expression by inhibiting accumulation of CIITA mRNA.