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Dependent Signal Transduction Pathway
1 Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston, MA, USA
2 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
3 Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston, MA, USA; Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: mccormic{at}helix.mgh.harvard.edu.
Salmonella typhimurium elicits an intense proinflammatory response characterized by movement of polymorphonuclear neutrophils (PMN) across the epithelial barrier to the intestinal lumen. We have previously shown that S. typhimurium, via the type III secretion system effector protein, SipA, initiates an ARF6 phospholipase D dependent lipid signaling cascade that directs activation of protein kinase C (PKC) and subsequent transepithelial movement of PMN. Here we sought to determine not only the specific PKC isoforms that are induced by the S. typhimurium effector, SipA, in model intestinal epithelia but also link the functional consequences of these isoforms to the promotion of PMN transepithelial migration. In vitro kinase PKC activation assays performed on polarized monolayers of T84 cells revealed that S. typhimurium and recombinant SipA (rSipA) induced the activation of PKC 
, 
, and 
isoforms. To elucidate which of these isoforms play a key role in mediating epithelial cell responses that lead to the observed PMN transepithelial migration we used a variety of PKC inhibitors with different isoform selectivity profiles. Inhibitors selective for PKC- (Go-6976 and HBDDE) markedly reduced S. typhimurium and rSipA-induced PMN transepithelial migration whereas inhibitors to either PKC (rottlerin) or PKC- (V1-2) failed to exhibit a significant decrease in transepithelial movement of PMN. These results were confirmed biochemically and by immunofluorescence coupled to confocal microscopy. Our results, herein, are the first to describe that the S. typhimurium effector protein, SipA, can activate multiple PKC isoforms but only PKC- is involved in the signal transduction cascade leading to PMN transepithelial migration.
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