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Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC--dependent signal transduction pathway

¹Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston 02129; ³Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115; and ²Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45367

Submitted 16 July 2003 ; accepted in final form 14 January 2004

Salmonella typhimurium elicits an intense proinflammatory response characterized by movement of polymorphonuclear neutrophils (PMN) across the epithelial barrier to the intestinal lumen. We previously showed that S. typhimurium, via the type III secretion system effector protein SipA, initiates an ADP-ribosylation factor-6- and 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 the specific PKC isoforms that are induced by the S. typhimurium effector SipA in model intestinal epithelia and to link the functional consequences of these isoforms in 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 induced activation of PKC-, -, and -. 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- (Gö-6976 and 2,2',3,3',4,4'-hexahydroxyl-1,1'-biphenyl-6,6'-dimethanoldimethyl ether) markedly reduced S. typhimurium- and recombinant SipA-induced PMN transepithelial migration, whereas inhibitors to 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 are the first to show 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.

inflammation; intestine; bacterial pathogenesis

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