IFN-gamma down-regulates TGF-beta1-induced IgA expression through Stat1 and p300 signaling.
IFN-gamma has been shown to either up- or down-regulate the expression of specific TGF-beta1-induced target genes. We investigated the effect of IFN-gamma on TGF-beta1-induced IgA isotype expression. We found that IFN-gamma inhibited not only TGF-beta1-induced germ-line (GL) alpha transcription, but also IgA secretion by TGF-beta1-stimulated murine B cells. Overexpression of Stat1 diminished TGF-beta1-induced, Smad3/4-and Runx3-mediated GL alpha 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 alpha transcription through binding to p300. Further, overexpression of SOCS1, a JAK inhibitor, diminished the antagonistic effect of IFN-gamma on TGF-beta1-induced GL alpha transcription and IgA secretion. These results indicate that JAK/Stat1-mediated IFN-gamma signaling antagonizes TGF-beta1-induced GL alpha transcription, mainly through deprivation of p300 from Smad3, resulting in decreased IgA synthesis.
Park
Seok-Rae
SR
Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon, 200-701, Korea.
Jung
Mee-Hyeun
MH
Jeon
Seong-Hyun
SH
Park
Mi-Hee
MH
Park
Kyoung-Hoon
KH
Lee
Mi-Ra
MR
Kim
Pyeung-Hyeun
PH
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015536:Down-Regulation; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051900:Smad3 Protein / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D007070:Immunoglobulin A; D050794:STAT1 Transcription Factor; D051900:Smad3 Protein; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse