Squelching the competition - STAT6 - mediated inhibition of IFN-γ inducibility

S. Goenka, J. Youn, L. Y. Yu-Lee, M. R. Boothby

Research output: Contribution to journalArticle

Abstract

Interferon gamma (IFN-γ) and interieukin 4 (IL-4) are key cytokines in the differentiation of helper T celts, exerting antagonistic effects on lymphocyte gene activation and the development of Th1 and Th2 immune responses. IFN-γ and IL-4 employ the Jak-Stat signaling pathway, using the Stat1 and Stat6 transcription factors respectively. We find that the IFN-γ-inducible interferon regulatory factor-1 (IRF-1) promoter is inhibited by activated Stat6 in a dose dependent manner, and this inhibition involves the Stat1 dependent GAS (gamma activation sequence) element of the IRF-1 promoter. Stat1 expression and its DNA binding ability are unchanged in the presence of activated Stat6, indicating intact proximal signaling. Importantly, a Stat6 C-terminal mutant lacking the transcription activation domain (TAD) binds to the IRF-1 GAS but does not inhibit the IRF-1 promoter. Thus, IRF-1 inhibition by Stat6 and IL-4 is not due to competition for DNA binding, however the Stat6 TAD may compete for a Stat1 co-activator, hence inhibiting Stat1 activity. The Stat6 mediated inhibition could not be reversed by CBP, a known Stat1 co-activator, suggesting the presence of another co-activator. These findings indicate that the antagonism between IFN-γ and IL-4 is in part due to competition for a limiting supply of a transcriptional co-activator.

Original languageEnglish
Pages (from-to)A1083
JournalFASEB Journal
Volume12
Issue number5
StatePublished - 1998 Mar 20

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Interferon Regulatory Factor-1
interferon-gamma
Interferon-gamma
interleukin-4
Interleukin-4
Chemical activation
Transcriptional Activation
promoter regions
transcriptional activation
Transcription
gene activation
Lymphocytes
DNA
binding capacity
Lymphocyte Activation
cytokines
Transcription Factors
lymphocytes
transcription factors
Genes

Cite this

Goenka, S., Youn, J., Yu-Lee, L. Y., & Boothby, M. R. (1998). Squelching the competition - STAT6 - mediated inhibition of IFN-γ inducibility. FASEB Journal, 12(5), A1083.
Goenka, S. ; Youn, J. ; Yu-Lee, L. Y. ; Boothby, M. R. / Squelching the competition - STAT6 - mediated inhibition of IFN-γ inducibility. In: FASEB Journal. 1998 ; Vol. 12, No. 5. pp. A1083.
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Goenka, S, Youn, J, Yu-Lee, LY & Boothby, MR 1998, 'Squelching the competition - STAT6 - mediated inhibition of IFN-γ inducibility', FASEB Journal, vol. 12, no. 5, pp. A1083.

Squelching the competition - STAT6 - mediated inhibition of IFN-γ inducibility. / Goenka, S.; Youn, J.; Yu-Lee, L. Y.; Boothby, M. R.

In: FASEB Journal, Vol. 12, No. 5, 20.03.1998, p. A1083.

Research output: Contribution to journalArticle

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AB - Interferon gamma (IFN-γ) and interieukin 4 (IL-4) are key cytokines in the differentiation of helper T celts, exerting antagonistic effects on lymphocyte gene activation and the development of Th1 and Th2 immune responses. IFN-γ and IL-4 employ the Jak-Stat signaling pathway, using the Stat1 and Stat6 transcription factors respectively. We find that the IFN-γ-inducible interferon regulatory factor-1 (IRF-1) promoter is inhibited by activated Stat6 in a dose dependent manner, and this inhibition involves the Stat1 dependent GAS (gamma activation sequence) element of the IRF-1 promoter. Stat1 expression and its DNA binding ability are unchanged in the presence of activated Stat6, indicating intact proximal signaling. Importantly, a Stat6 C-terminal mutant lacking the transcription activation domain (TAD) binds to the IRF-1 GAS but does not inhibit the IRF-1 promoter. Thus, IRF-1 inhibition by Stat6 and IL-4 is not due to competition for DNA binding, however the Stat6 TAD may compete for a Stat1 co-activator, hence inhibiting Stat1 activity. The Stat6 mediated inhibition could not be reversed by CBP, a known Stat1 co-activator, suggesting the presence of another co-activator. These findings indicate that the antagonism between IFN-γ and IL-4 is in part due to competition for a limiting supply of a transcriptional co-activator.

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