INHIBITION OF LEUKOCYTE EMIGRATION INDUCED DURING THE SYSTEMIC INFLAMMATORY REACTION IN-VIVO IS NOT DUE TO IL-8

In keeping with the multistep model of leukocyte-endothelial cell inte raction, stimulation of endothelium by cytokines or endotoxin (LPS) in vitro leads to selectin/integrin-mediated neutrophil adhesion, follow ed by neutrophil endothelial transmigration, The i.p. injection of LPS in vivo induces a systemic inflammatory reaction in a mouse model wit h generalized activation of both endothelial cells (up-regulation of a dhesion molecules ICAM-1, VCAM-1, E-selectin) and neutrophils (up-regu lation of Mac-1). However, no intravascular endothelial adhesion or ti ssue emigration of neutrophils can be observed, Even more importantly, the in vivo emigration of polymorphonuclear cells at sites of a local inflammatory reaction (IL-8, TNF, LPS) is totally inhibited when the mice are pretreated systemically with LPS, although the neutrophils re spond fully to a rechallenge with LPS ex vivo, and endothelial adhesio n molecules are further up-regulated locally, The systemic application of TNF also caused a total inhibition of neutrophil emigration. Howev er, while anti-TNF mAb abrogated the inhibitory activity induced by TN F, they had no effect on systemic LPS. The systemic application of IL- 8 did not inhibit neutrophil emigration, nor did the pretreatment of m ice with anti-IL-8 mAb before the systemic application of LPS abrogate the inhibitory activity induced by LPS, Therefore, the putative inhib itor of neutrophil emigration, which may be of great physiologic impor tance, as it prevents in vivo the generalized emigration of activated neutrophils, mast likely is not IL-8.