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J. Biol. Chem., Vol. 275, Issue 37, 29132-29137, September 15, 2000
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From the Interleukins 4 and 13 can affect their target
cells by activation of signal transducer and activator of transcription
6 (STAT 6) or phosphatidylinositol 3-kinase (PI3K). We examined
the signal transduction events involved in IL-4 and IL-13 regulation of
epithelial paracellular permeability using T84 cells, a model human
colonic epithelium. T84 cells treated with IL-4 or IL-13
displayed virtually identical dose- and time-dependent STAT
6 activation as assessed by electrophoretic mobility shift assay (EMSA)
and decreases in transepithelial resistance (TER). STAT 6 DNA binding
activity was maximal in nuclear extracts 30 min after exposure to IL-4 or IL-13, and TER was maximally reduced by 24 h post-treatment. Pretreatment of epithelia with transcription factor decoys
(phosphorothioated DNA oligonucleotides containing the STAT 6 binding
site) dramatically reduced STAT 6 activation as detected by EMSA, but
did not attenuate the TER reduction by IL-4 or IL-13. In contrast,
although the PI3K inhibitors wortmannin and LY294002 did not affect
IL-4 or IL-13 STAT 6 activation, they significantly inhibited the
ability of either cytokine to lower TER. Thus, we provide evidence for PI3K as the major proximal signaling event in IL-4 and IL-13 regulation of TER and speculate that pharmacological targeting of enterocytic PI3K
activity may represent a means to manipulate epithelial permeability.
Interleukins 4 and 13 Increase Intestinal Epithelial Permeability
by a Phosphatidylinositol 3-Kinase Pathway
LACK OF EVIDENCE FOR STAT 6 INVOLVEMENT*
,¶
Intestinal Disease Research Programme and
§ Infection and Immunity Programme, McMaster University,
Hamilton, Ontario L8N 3Z5, Canada
*
Financial support was provided by an operating grant
(MT-13421) from the Medical Research Council of Canada (to D. M. M.).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.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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