IFN-γ down-regulates TGF-β1-induced IgA expression through Stat1 and p300 signaling
2010
Park, S.R., Kangwon National University, Chuncheon, Republic of Korea | Jung, M.H., Kangwon National University, Chuncheon, Republic of Korea | Jeon, S.H., Hans Biomed Corporation Daedeok RnD Center, Daejeon, Republic of Korea | Park, M.H., Kangwon National University, Chuncheon, Republic of Korea | Park, K.H., Kangwon National University, Chuncheon, Republic of Korea | Lee, M.R., Kangwon National University, Chuncheon, Republic of Korea | Kim, P.H., Kangwon National University, Chuncheon, Republic of Korea
IFN-γ has been shown to either up- or down-regulate the expression of specific TGF-β1-induced target genes. We investigated the effect of IFN-γ on TGF-β1-induced IgA isotype expression. We found that IFN-γ inhibited not only TGF-β1-induced germ-line (GL) α transcription, but also IgA secretion by TGF-β1-stimulated murine B cells. Overexpression of Stat1 diminished TGF-β1-induced, Smad3/4-and Runx3-mediated GLα promoter activity. Overexpression of p300 also increased the promoter activity, while its effect was abrogated by co-transfected Stat1. Stat1 interfered with the Smad3:p300 interaction, likely due to a stronger Stat1:p300 binding affinity. These results indicate that Stat1 can inhibit GLα transcription through binding to p300. Further, overexpression of SOCS1, a JAK inhibitor, diminished the antagonistic effect of IFN-γ on TGF-β1-induced GLα transcription and IgA secretion. These results indicate that JAK/Stat1-mediated IFN-γ signaling antagonizes TGF-β1-induced GLα transcription, mainly through deprivation of p300 from Smad3, resulting in decreased IgA synthesis.
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