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1 Medicine, University of Chicago, Chicago, IL, USA
2 Pediatrics, University of Chicago, Chicago, IL, USA
3 Surgery, Harvard University, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: mmusch{at}medicine.bsd.uchicago.edu.
We determined if the cytoprotective heat shock protein, hsp72, protects against the injurious effects of Clostridium difficile toxin A (TxA) on intestinal epithelial cells. Colonic epithelial Caco2/bbe (C2) cells were stably transfected with hsp72 anti-sense (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 TER, increase in [3H]-mannitol flux, and increase 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 if ATP depletion decreases TER, cells were treated with antimycin, A which caused a decline in TER. In conclusion, hsp72 may protect intestinal epithelial cells from TxA-mediated damage through several mechanisms including actin stabilization, mitochondrial protection, inhibition of apoptosis activation, but not by prevention of RhoA glucosylation.
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