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Am J Physiol Cell Physiol. 2003 Apr;284(4):C1073-82. Epub 2002 Dec 18.

Protective role of HSP72 against Clostridium difficile toxin A-induced intestinal epithelial cell dysfunction.

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The Martin Boyer Research Laboratories of the Inflammatory Bowel Disease Research Center, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.


We determined whether the cytoprotective heat shock protein HSP72 protects against the injurious effects of Clostridium difficile toxin A (TxA) on intestinal epithelial cells. Colonic epithelial Caco-2/bbe (C2) cells were stably transfected with HSP72 antisense (C2AS) or vector only (C2VC), resulting in low and high HSP72 expression, respectively. Measurements of epithelial barrier integrity, mitochondrial function, and apoptosis activation were assessed after TxA exposure. HSP72 and RhoA interactions were evaluated with immunoprecipitations. In C2AS cells, TxA was associated with a greater decrease in transepithelial resistance (TER), an increase in [(3)H]mannitol flux, and increased dissociation of perijunctional actin. Although HSP72 binds RhoA, it failed to prevent RhoA glucosylation. TxA caused a more rapid decrease in ATP, release of cytochrome c, and activation of caspase-9 in C2AS cells. To determine whether ATP depletion decreases TER, we treated cells with antimycin A, which caused a decline in TER. We conclude that HSP72 may protect intestinal epithelial cells from TxA-mediated damage through several mechanisms, including actin stabilization, mitochondrial protection, and inhibition of apoptosis activation, but not by prevention of RhoA glucosylation.

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