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J Pharmacol Exp Ther. 2005 Jul;314(1):155-61. Epub 2005 Mar 18.

A novel inhibitor of N-ethylmaleimide-sensitive factor decreases leukocyte trafficking and peritonitis.

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  • 1Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

Endothelial exocytosis is an early stage in the process of leukocyte trafficking. N-ethylmaleimide-sensitive factor (NSF) plays a critical role in regulating exocytosis. We hypothesized that inhibitors of NSF decrease endothelial exocytosis and vascular inflammation. We designed a novel fusion polypeptide consisting of a human immunodeficiency virus transactivator of transcription (TAT) protein transduction domain joined to a NSF homohexamerization domain. We show that this TAT-NSF polypeptide inhibits the ATPase activity and the disassembly activity of NSF. Furthermore, the TAT-NSF polypeptide decreases endothelial cell exocytosis and reduces leukocyte adherence to endothelial cells in culture. Finally, the TAT-NSF polypeptide inhibits leukocyte rolling on murine venules in vivo and inhibits leukocyte trafficking into the peritoneal cavity in a murine model of experimental peritonitis. These data suggest that NSF is a critical regulator of leukocyte trafficking in vivo. Novel compounds that inhibit the exocytic machinery in endothelial cells may be useful anti-inflammatory drugs.

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