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      STAT1-Independent Down-Regulation of Interferon-Gamma-Induced Class II Transactivator and HLA-DR Expression by Transforming Growth Factor Beta-1 in Human Glomerular Endothelial Cells

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          Background: The competition between STAT1 and Smad3 for a limiting amount of the nuclear protein p300, a transcriptional coactivator, was suggested to be a mechanism for the antagonism between interferon-γ (IFN-γ) and transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>). We investigated the effect of TGF-β<sub>1</sub> on IFN-γ-induced HLA-DR production in cultured human glomerular endothelial cells (HGECs), and the involvement of p300 in this process. Methods: Cell surface expression of HLA-DR and mRNA levels of HLA-DR and class II transactivator (CIITA), the master regulator of HLA-DR gene transcription, were measured by cellular ELISA and Northern blot, respectively. The levels of STAT1 and Smad3 protein were analyzed by Western blot. Nuclear binding activity of STAT1 was assessed by electrophoretic mobility shift assay. Results: IFN-γ increased the cell surface expression of HLA-DR along with increases in the mRNA levels of CIITA and HLA-DR, while these stimulatory effects of IFN-γ were down-regulated by TGF-β<sub>1</sub>. IFN-γ increased phosphorylation of STAT1 and this activation was not inhibited by TGF-β<sub>1</sub>. IFN-γ increased binding of p-STAT1 to p300, while TGF-β<sub>1</sub> increased binding of Smad3 to p300. TGF-β<sub>1</sub>-induced Smad3 binding to p300 was inhibited by IFN-γ, whereas IFN-γ-induced p-STAT1 binding to p300 was not inhibited by TGF-β<sub>1</sub>. IFN-γ increased DNA binding activity of STAT1. Inhibition of interaction between STAT1 and p300 by addition of anti-p300 antibody to nuclear extract down-regulated DNA binding activity of STAT1. In contrast, TGF-β<sub>1</sub> did not inhibit IFN-γ-induced STAT1 binding to DNA. Conclusions: TGF-β<sub>1</sub> down-regulated IFN-γ-induced CIITA and HLA-DR expression in HGECs. Though there was an antagonism between IFN-γ and TGF-β<sub>1</sub>, the competition for p300 between p-STAT1 and Smad3 was not the mechanism for it.

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          Most cited references 17

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          MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation.

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            Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1.

            CIITA is the mediator of MHC class II gene induction by interferon-gamma (IFNgamma). The CIITA gene is itself selectively activated via one of its four promoters (PIV). We show here that three cis-acting elements, the GAS, the E box, and the IRF-1-binding site, as well as the transacting factors Stat1 and IRF-1, are essential for activation of CIITA promoter IV by IFNgamma. Stat1 binds to the GAS site only in the presence of the ubiquitous factor USF-1, which binds to the adjacent E box. Indeed, Stat1 and USF-1 bind to the GAS/E box motif in a cooperative manner. The specificity for CIITA activation by IFNgamma is thus dictated by the GAS/E box motif and by the selective interaction of IFNgamma-activated Stat1 and USF-1. This clarifies the missing link in the overall pathway of IFNgamma activation of MHC-II expression.
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              Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes

              The class II transactivator (CIITA) has been shown to be required for major histocompatibility complex (MHC) class II gene expression in B cells and its deficiency is responsible for a hereditary MHC class II deficiency. Here we show that CIITA is also involved in the inducible expression of class II genes upon interferon gamma (IFN-gamma) treatment. The expression of CIITA is also inducible with IFN-gamma before the induction of MHC class II mRNA. In addition, CIITA mRNA expression does not require new protein synthesis, although new protein synthesis is necessary for the transcription of class II. This suggests that synthesis of new CIITA protein may be essential to induce class II gene expression. We also showed that the JAK1 protein tyrosine kinase activity is required to induce the expression of CIITA upon IFN-gamma stimulation. This finding indicates that CIITA is part of the signaling cascade from the IFN-gamma receptor to the activation of class II genes. In addition, the expression of CIITA is sufficient to activate class II genes in the absence of IFN-gamma stimulation suggesting that CIITA is the major regulatory factor for the inducible expression of class II genes. Together, these data suggest that CIITA is the IFN- inducible cycloheximide sensitive factor previously shown to be required for the induction of MHC class II gene expression.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                July 2005
                15 April 2005
                : 100
                : 3
                : e124-e131
                Departments of Internal Medicine and Urology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
                85058 Nephron Exp Nephrol 2005;100:e124–e131
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 23, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/85058
                Original Paper


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