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J. Biol. Chem., Vol. 277, Issue 6, 4247-4254, February 8, 2002
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From the Division of Gastroenterology, Beth Israel Deaconess
Medical Center, Harvard Medical School,
Boston, Massachusetts 02215
Clostridium difficile toxin A
increases paracellular permeability in colonic epithelial T84 cells by
mechanisms involving RhoA glucosylation and actin depolymerization.
However, we previously observed that toxin A-mediated decline in
transepithelial electrical resistance preceded changes in cell
morphology and tight junction ultrastructure (Hecht, G., Pothoulakis,
C., LaMont, J. T., and Madara, J. L. (1988) J. Clin. Invest. 82, 1516-1524). Recent studies also showed that
C. difficile toxins induce early cellular responses, including activation of mitogen-activated protein kinases, generation of reactive oxygen metabolites, and calcium influx. The aim of this
study was to investigate whether toxin A-induced early cellular responses contribute to the permeability changes. We found that toxin A
stimulated the activities of membrane and cytosolic protein kinase C This work has been presented in a preliminary form at the American
Gastroenterological Association Digestive Disease Week in Atlanta,
Georgia, May 20, 2001.
Protein Kinase C Signaling Regulates ZO-1 Translocation and
Increased Paracellular Flux of T84 Colonocytes Exposed to
Clostridium difficile Toxin A*
(PKC) and cytosolic PKC
. A specific PKC/ antagonist (myristoylated PKC/ peptide) blocked toxin A-mediated RhoA
glucosylation. Furthermore, decreased transepithelial electrical
resistance and increased translocation of ZO-1 from tight junction
occurred within 2-3 h of toxin A exposure and were also inhibited by
PKC/ antagonist. During this time period, toxin exposure did not
induce translocation of ZO-2, dephosphorylation or translocation of
occludin, or cell rounding. Our data indicate that PKC signaling
regulates toxin A-mediated paracellular permeability changes and ZO-1 translocation.
*
This work was supported by National Institute of Health
Grants (DK 34583 and DK 47343) and a pilot feasibility study award from
the Center for the Study of Inflammatory Bowel Disease at Massachusetts
General Hospital (DK 43351) (to M. L. C.).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: Division of
Gastroenterology, DANA 501, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-8377; Fax: 617-975-5071; E-mail: jlamont@caregroup.harvard.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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