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J. Biol. Chem., Vol. 277, Issue 41, 38254-38261, October 11, 2002
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From the STAT6 functions as a critical mediator of
IL-4-stimulated gene activation, and the function of STAT6 is regulated
by both tyrosine and serine kinase activities. Here we analyzed the
role of serine phosphorylation in regulation of STAT6-mediated
transcription. Optimal transcriptional response of IL-4-inducible
promoters requires costimulatory signals through CD40-stimulated
intracellular kinases such as p38 MAPK. We found that the p38 MAPK
inhibitor SB202190 as well as the dominant negative p38 MAPK inhibited
interleukin (IL)-4 regulated expression of CD23 in Ramos B cells. IL-4
stimulation did not stimulate p38 MAPK activity, but inhibition of p38
MAPK activity directly correlated with inhibition of IL-4-induced gene activation. Dissection of individual response elements on
IL-4-regulated promoter showed that C/EBP
p38 Mitogen-activated Protein Kinase Regulates
Interleukin-4-induced Gene Expression by Stimulating
STAT6-mediated Transcription*
§,,,§
Institute of Medical Technology, University
of Tampere, FIN-33014 Tampere, Finland, the § Department
of Clinical Microbiology, Tampere University Hospital, FIN-33521
Tampere, Finland, and the ¶ Department of Pathology,
University of Tampere, FIN-33014 Tampere, Finland
-mediated transcription was
insensitive to SB202190 treatment in B cells whereas STAT6-mediated
transcription was regulated by p38 MAPK. The IL-4-induced immediate
activation events of STAT6 were not affected by p38 MAPK activity.
Furthermore, phosphoamino acid analysis and phosphopeptide mapping
indicated that STAT6 is not a direct substrate for p38 MAPK. Instead,
p38 MAPK was found to directly regulate the activity of the
transactivation domain of STAT6. These results show that, in addition
to the well established proinflammatory effects, p38 MAPK also provides
a costimulatory signal for IL-4-induced gene responses by directly stimulating the transcriptional activation of STAT6.
*
This work was supported by the Medical Research Fund of
Tampere University Hospital, the Academy of Finland, Tampere University Foundation, The Finnish Cultural Foundation, The Centenary Foundation of Kymi Corporation, The Finnish Cancer Foundation, The Tampere Tuberculosis Foundation, and the Sigrid Juselius Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Institute of
Medical Technology, University of Tampere, FIN-33014, Finland. Tel.: 358-3-215-7845; Fax: 358-3-215-7710; E-mail:
olli.silvennoinen@uta.fi.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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