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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 494-502
Interleukin-4-induced transcriptional activation by Stat6 involves
multiple serine/threonine kinase pathways and serine phosphorylation of
Stat6
Marko Pesu,
Kati Takaluoma,
Saara Aittomäki,
Anssi Lagerstedt,
Kalle Saksela,
Panu E. Kovanen, and
Olli Silvennoinen
From the Laboratory of Molecular Immunology, Department of
Pathology, Laboratory of Molecular Medicine, Institute of Medical
Technology, University of Tampere, and the Department of Clinical
Microbiology, Tampere University Hospital, Finland.
Stat6 transcription factor is a critical mediator of IL-4-specific
gene responses. Tyrosine phosphorylation is required for nuclear
localization and DNA binding of Stat6. The authors investigated whether
Stat6-dependent transcriptional responses are regulated through
IL-4-induced serine/threonine phosphorylation. In Ramos B
cells, the serine/threonine kinase inhibitor H7 inhibited IL-4-induced expression of CD23. Treatment with H7 did not affect IL-4R-mediated immediate signaling events such as tyrosine phosphorylation of Jak1,
Jak3, insulin receptor substrate (IRS)-1 and IRS-2, or tyrosine phosphorylation and DNA binding of Stat6. To analyze whether the H7-sensitive pathway was regulating Stat6-activated transcription, we
used reporter constructs containing different IL-4 responsive elements.
H7 abrogated Stat6-, as well as Stat5-, mediated reporter gene
activation and partially reduced C/EBP-dependent reporter activity. By
contrast, IL-4-induced transcription was not affected by wortmannin, an
inhibitor of the phosphatidyl-inositol 3'-kinase pathway. Phospho-amino
acid analysis and tryptic phosphopeptide maps revealed that IL-4
induced phosphorylation of Stat6 on serine and tyrosine residues in
Ramos cells and in 32D cells lacking endogenous IRS proteins. However,
H7 treatment did not inhibit the phosphorylation of Stat6. Instead, H7
inhibited the IL-4-induced phosphorylation of RNA polymerase II. These
results indicate that Stat6-induced transcription is dependent on
phosphorylation events mediated by H7-sensitive kinase(s) but that it
also involves serine phosphorylation of Stat6 by an H7-insensitive
kinase independent of the IRS pathway.
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