A Novel Inhibitor of N-Ethylmaleimide-Sensitive Factor Decreases Leukocyte Trafficking and Peritonitis

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 314; no. 1; pp. 155 - 161
• Main Authors: Morrell, Craig N, Matsushita, Kenji, Lowenstein, Charles J
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.2005
• Subjects: Animals; Endothelial Cells - drug effects; Exocytosis - drug effects; Leukocyte Rolling - drug effects; Leukocytes - drug effects; Mice; Mice, Inbred C57BL; N-Ethylmaleimide-Sensitive Proteins; Peritoneal Cavity - cytology; Peritonitis - drug therapy; Peritonitis - pathology; Receptors, Leukocyte-Adhesion - drug effects; SNARE Proteins; Venules - cytology; Vesicular Transport Proteins - antagonists & inhibitors; Vesicular Transport Proteins - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.082529

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.