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© The Rockefeller University Press, 0021-9525/2003/5/641 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 641-651

PMN transendothelial migration decreases nuclear NFB in IL-1ß–activated endothelial cells

Gediminas Cepinskas, Jurate Savickiene, Carmen V. Ionescu and Peter R. Kvietys

Program in Vascular Biology/Inflammation, Lawson Health Research Institute, London, Ontario, Canada N6A 4G5

Address correspondence to Peter R. Kvietys, Program in Vascular Biology/Inflammation, Lawson Health Research Institute, 375 South Street, Room C210, London, Ontario, Canada N6A 4G5. Tel.: (519) 685-8300 ext. 77055. Fax: (519) 667-6629. E-mail: pkvietys{at}julian.uwo.ca

During the systemic inflammatory response, circulating cytokines interact with the vascular endothelium, resulting in activation and nuclear accumulation of the nuclear transcription factor, nuclear factor kappa B (NFB). In turn, NFB transactivates relevant proinflammatory genes, resulting in an amplification of the inflammatory response. Because this scenario is potentially detrimental to the host, mechanisms exist to limit this amplification. Using an in vitro system that mimics the vascular–interstitial interface during inflammation (cell culture inserts), we provide evidence for the existence of a novel negative feedback mechanism on NFB activity. We show that the interleukin 1ß–induced accumulation of nuclear NFB in human umbilical vein endothelial cell monolayers is dramatically reduced when polymorphonuclear leukocytes (PMN) are allowed to migrate across these monolayers. This effect does not appear to be due to PMN-derived elastase or nitric oxide. Fixed PMN (adhere but do not migrate) did not affect nuclear NFB. Furthermore, cross-linking of platelet-endothelial cell adhesion molecule-1 (PECAM-1), but not intercellular adhesion molecule-1, reduces human umbilical vein endothelial cell nuclear NFB induced by interleukin 1ß. Finally, interaction of PMN with PECAM-1–deficient endothelial cells does not reduce nuclear NFB. These observations indicate that engagement of PECAM-1 by emigrating PMN is a pivotal event in this negative feedback on NFB activity.

Key Words: ICAM-1; CD18; HUVEC; mice; NO

^* Abbreviations used in this paper: CD18, cluster of differentiation-18; CLP, cecal ligation and perforation; EMSA, electrophoretic mobility shift assay; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule 1; IB, inhibitory protein kappa B; IL-1ß, interleukin 1ß; LPS, lipopolysaccharide; MPO, myeloperoxidase; NFB, nuclear factor kappa B; NO, nitric oxide; PAF, platelet-activating factor; PECAM-1, platelet-endothelial cell adhesion molecule 1; PMN, polymorphonuclear leukocytes; TNF-, tumor necrosis factor .

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