CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen

Buka Samten, James C. Townsend, Stephen Weis, Anindita Bhoumik, Peter Klucar, Homayoun Shams, Peter F. Barnes

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Abstract

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.

Original languageEnglish
Pages (from-to)2056-2064
Number of pages9
JournalJournal of Immunology
Volume181
Issue number3
StatePublished - 1 Aug 2008

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Transcription Factor AP-1
T-Lymphocytes
Antigens
Transcription Factors
Cyclic AMP Response Element Modulator
Activating Transcription Factor 1
Cyclic AMP Response Element-Binding Protein
Chromatin Immunoprecipitation
Transcription Initiation Site
Mycobacterium tuberculosis
Small Interfering RNA
Up-Regulation
Peptides

Cite this

Samten, B., Townsend, J. C., Weis, S., Bhoumik, A., Klucar, P., Shams, H., & Barnes, P. F. (2008). CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen. Journal of Immunology, 181(3), 2056-2064.
Samten, Buka ; Townsend, James C. ; Weis, Stephen ; Bhoumik, Anindita ; Klucar, Peter ; Shams, Homayoun ; Barnes, Peter F. / CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen. In: Journal of Immunology. 2008 ; Vol. 181, No. 3. pp. 2056-2064.
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Samten, B, Townsend, JC, Weis, S, Bhoumik, A, Klucar, P, Shams, H & Barnes, PF 2008, 'CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen', Journal of Immunology, vol. 181, no. 3, pp. 2056-2064.

CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen. / Samten, Buka; Townsend, James C.; Weis, Stephen; Bhoumik, Anindita; Klucar, Peter; Shams, Homayoun; Barnes, Peter F.

In: Journal of Immunology, Vol. 181, No. 3, 01.08.2008, p. 2056-2064.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Samten, Buka

AU - Townsend, James C.

AU - Weis, Stephen

AU - Bhoumik, Anindita

AU - Klucar, Peter

AU - Shams, Homayoun

AU - Barnes, Peter F.

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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.

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