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Originally published In Press as doi:10.1074/jbc.M106226200 on September 10, 2001
J. Biol. Chem., Vol. 276, Issue 50, 47563-47574, December 14, 2001
Phosphatidylinositol
3-Kinase-dependent Pathways Oppose Fas-induced
Apoptosis and Limit Chloride Secretion in Human Intestinal
Epithelial Cells
IMPLICATIONS FOR INFLAMMATORY DIARRHEAL STATES*
Maria T.
Abreu §,
Elizabeth T.
Arnold ,
Jimmy Y. C.
Chow¶, and
Kim E.
Barrett¶
From the Inflammatory Bowel Disease Center and Burns
and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles,
California 90048 and the ¶ Division of Gastroenterology,
University of California, San Diego, School of Medicine,
San Diego, California 92103
The epithelial lining of the
intestine serves as a barrier to lumenal bacteria and can be
compromised by pathologic Fas-mediated epithelial apoptosis.
Phosphatidylinositol (PI)3-kinase signaling has been described to limit
apoptosis in other systems. We hypothesized that
PI3-kinase-dependent pathways regulate Fas-mediated
apoptosis and barrier function in intestiynal epithelial cells (IEC).
IEC lines (HT-29 and T84) were exposed to agonist anti-Fas
antibody in the presence or absence of chemical inhibitors of
PI3-kinase (LY294002 and wortmannin). Apoptosis, barrier function,
changes in short circuit current ( Isc), and
expression of adhesion molecules were assessed. Inhibition of
PI3-kinase strongly sensitized IEC to Fas-mediated apoptosis.
Expression of constitutively active Akt, a principal downstream
effector of the PI3-kinase pathway, protected against Fas-mediated
apoptosis to an extent that was comparable with expression of a genetic
caspase inhibitor, p35. PI3-kinase inhibition sensitized to
apoptosis by increasing and accelerating Fas-mediated caspase
activation. Inhibition of PI3-kinase combined with cross-linking Fas
was associated with increased permeability to molecules that were <400
Da but not those that were >3,000 Da. Inhibition of PI3-kinase
resulted in chloride secretion that was augmented by
cross-linking Fas. Confocal analyses revealed polymerization of actin
and maintenance of epithelial cell adhesion molecule-mediated
interactions in monolayers exposed to anti-Fas antibody in the context
of PI3-kinase inhibition. PI3-kinase-dependent pathways,
especially Akt, protect IEC against Fas-mediated apoptosis.
Inhibition of PI3-kinase in the context of Fas signaling results in
increased chloride secretion and barrier dysfunction. These findings
suggest that agonists of PI3-kinase such as growth factors may have a
dual effect on intestinal inflammation by protecting epithelial cells
against immune-mediated apoptosis and limiting chloride
secretory diarrhea.
*
This work was supported by Grants K08 DK02635 and 1R03
DK59469 from the Natonal Institutes of Health (to M. T. A.), a Crohn's and Colitis Foundation of America First Award
(to M. T. A.), and Grant DK 28305 from the Natonal Institutes
of Health (to K. E. B.). Some of this work was performed
using a laser scanning confocal microscope provided by Grant
NCRR 1 S10 RR13717-01 from the Natonal Institutes of Health.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: Inflammatory Bowel
Disease Center, Cedars-Sinai Medical Center, 8631 West 3rd
St., Suite 245E, Los Angeles, CA 90048. Tel.: 310-423-4100; Fax: 310-423-0147; E-mail: Maria.Abreu@cshs.org.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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