TY - JOUR
T1 - CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen
AU - Samten, Buka
AU - Townsend, James C.
AU - Weis, Steven E.
AU - Bhoumik, Anindita
AU - Klucar, Peter
AU - Shams, Homayoun
AU - Barnes, Peter F.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - IFN-γ production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-γ, -73 to -48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN-γ in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN-γ upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN-γ proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN-γ and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN-γ proximal promoter and that they up-regulate IFN-γ transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.
AB - IFN-γ production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-γ, -73 to -48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN-γ in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN-γ upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN-γ proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN-γ and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN-γ proximal promoter and that they up-regulate IFN-γ transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.
UR - http://www.scopus.com/inward/record.url?scp=49649120693&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.181.3.2056
DO - 10.4049/jimmunol.181.3.2056
M3 - Article
C2 - 18641343
AN - SCOPUS:49649120693
SN - 0022-1767
VL - 181
SP - 2056
EP - 2064
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -