IFN- γ Down-Regulates TGF- β 1-Induced IgA Expression through Stat1 and p300 Signaling

IFN- γ has been shown to either up- or down-regulate the expression of specific TGF- β 1-induced target genes. We investigated the effect of IFN- γ on TGF- β 1-induced IgA isotype expression. We found that IFN- γ inhibited not only TGF- β 1-induced germ-line (GL) α transcription, but also IgA secretion by TGF- β 1-stimulated murine B cells. Overexpression of Stat1 diminished TGF- β 1-induced, Smad3/4- and Runx3-mediated GL α 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 GL α transcription through binding to p300. Further, overexpression of SOCS1, a JAK inhibitor, diminished the antagonistic effect of IFN- γ on TGF- β 1-induced GL α transcription and IgA secretion. These results indicate that JAK/Stat1-mediated IFN- γ signaling antagonizes TGF- β 1-induced GL α transcription, mainly through deprivation of p300 from Smad3, resulting in decreased IgA synthesis.