Stat6 inhibits human interleukin-4 promoter activity in T cells

S. N. Georas, J. E. Cumberland, T. F. Burke, R. Chen, U. Schindler, V. Casolaro

Research output: Contribution to journalArticle

Abstract

The differentiation of naive T-helper (Th) cells into cytokine-secreting effector Th cells requires exposure to multiple signals, including exogenous cytokines. Interleukin-4 (IL-4) plays a major role in this process by promoting the differentiation of IL-4-secreting Th2 cells. In Th2 cells, IL- 4 gene expression is tightly controlled at the level of transcription by the coordinated binding of multiple transcription factors to regulatory elements in the proximal promoter region. Nuclear factor of activated T cell (NFAT) family members play a critical role in regulating IL-4 transcription and interact with up to five sequences (termed P0 through P4) in the IL-4 promoter. The molecular mechanisms by which IL-4 induces expression of the IL-4 gene are not known, although the IL-4-activated transcription factor signal transducer and activator of transcription 6 (Stat6) is required for this effect. We report here that Stat6 interacts with three binding sites in the human IL-4 promoter by electrophoretic mobility shift assays. These sites overlap the P1, P2, and P4 NFAT elements. To investigate the role of Stat6 in regulating IL-4 transcription, we used Stat6-deficient Jurkat T cells with different intact IL-4 promoter constructs in cotransfection assays. We show that, whereas a multimerized response element from the germline IgE promoter was highly induced by IL-4 in Stat6-expressing Jurkat cells, the intact human IL-4 promoter was repressed under similar conditions. We conclude that the function of Stat6 is highly dependent on promoter context and that this factor promotes IL-4 gene expression in an indirect manner.

Original languageEnglish (US)
Pages (from-to)4529-4538
Number of pages10
JournalBlood
Volume92
Issue number12
StatePublished - Dec 15 1998

ASJC Scopus subject areas

  • Hematology

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    Georas, S. N., Cumberland, J. E., Burke, T. F., Chen, R., Schindler, U., & Casolaro, V. (1998). Stat6 inhibits human interleukin-4 promoter activity in T cells. Blood, 92(12), 4529-4538.