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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4529-4538
RAPID COMMUNICATION
Stat6 Inhibits Human Interleukin-4 Promoter Activity in T Cells
Steve N. Georas,
John E. Cumberland,
Thomas F. Burke,
Rongbing Chen,
Ulrike Schindler, and
Vincenzo Casolaro
From the Divisions of Pulmonary and Critical Care Medicine and
Allergy and Clinical Immunology, The Johns Hopkins University Asthma
and Allergy Center, Baltimore, MD; and Tularik Inc, South San
Francisco, CA.
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.
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