Regulation of the activity of IFN-gamma promoter elements during Th cell differentiation.
Before they can deliver their effector functions, CD4+ Th cells must differentiate into Th1 or Th2 subsets. We have prepared reporter transgenic mice that express the luciferase gene under the control of proximal (prox.IFN-gamma) and distal (dist.IFN-gamma) regulatory elements from the IFN-gamma promoter to permit investigation of mechanisms that regulate IFN-gamma gene transcription during Th cell differentiation. Precursor Th cells (pTh) contain high levels of cAMP response element binding protein-activation transcription factor-1 (CREB-ATF1) proteins that bind these promoter elements from the IFN-gamma gene, and these cells fail to express promoter activity. Restimulated effector Th (eTh) cells have reduced levels of CREB-ATF1 proteins, their nuclear extracts exhibit reduced CREB-ATF1 binding and greater Jun and Jun-ATF2 binding to dist.IFN-gamma), and eTh cells express promoter activity. CREB directly competes with effector T cell nuclear proteins for dist.IFN-gamma binding, and overexpression of CREB inhibits both prox.IFN-gamma- and dist.IFN-gamma-directed transcription in Jurkat T cells. IL-12-stimulated Thl differentiation increases dist.IFN-gamma activity in restimulated eTh1 cells; eTh1 nuclear extracts form increased levels of Jun-ATF2-dist.IFN-gamma complexes. Taken together, these data suggest that both de-repression and trans-activation contribute to the induction of IFN-gamma gene transcription during Th1 differentiation.
Zhang
F
F
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Wang
D Z
DZ
Boothby
M
M
Penix
L
L
Flavell
R A
RA
Aune
T M
TM
D000818:Animals; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D018664:Interleukin-12; D007371:Interferon-gamma