TGF-beta attenuates the class II transactivator and reveals an accessory pathway of IFN-gamma action.
In the present report, the induction of the HLA-DRA gene in response to IFN-gamma is shown to be selectively attenuated by TGF-beta. Thus, the accumulation in response to IFN-gamma of mRNA for the DRA gene, but not for the guanylate binding protein-2 gene, is markedly reduced in the presence of TGF-beta. Moreover, the data presented show that the mechanism by which TGF-beta inhibits expression of DRA involves attenuation of the class II transactivator (CIITA) gene. This conclusion is based on the finding that induction of CIITA gene expression in response to IFN-gamma is completely abrogated in TGF-beta-treated cells. In contrast, TGF-beta did not affect IFN-gamma-induced tyrosine phosphorylation of Jak1, Jak2, or the signal transducer and activator of transcription-1 (Stat1). TGF-beta also did not inhibit the appearance of IFN-gamma-activated, Stat1 DNA-binding activity in intact cells. Thus, the effects of TGF-beta on CIITA could not be explained by altered signaling through Jak-Stat1. Potential alternative targets for the inhibitory effects of TGF-beta were identified in renaturation tyrosine kinase assays, which revealed three IFN-gamma-activated protein tyrosine kinases that, in contrast to the Janus kinases, are sensitive to TGF-beta. These findings 1) indicate that inhibition of MHC class II gene expression by TGF-beta involves attenuation of the CIITA gene independently of effects on Janus kinases, 2) provide direct evidence that IFN-gamma activates both Janus and non-Janus protein tyrosine kinases, and 3) identify an accessory pathway of IFN-gamma action involving tyrosine kinases that, unlike the Jak-Stat1 pathway, are impaired by TGF-beta.
Nandan
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Department of Medicine (Division of Infectious Diseases), University of British Columbia Faculty of Medicine, Vancouver, Canada.
Reiner
N E
NE
D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics*; D059805:HLA-DR alpha-Chains; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D009687:Nuclear Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D019000:Phosphotyrosine; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2