Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature

The initiating step of neutrophil-induced cytotoxicity in the liver is the recruitment of these phagocytes into sinusoids. The aim of our study was to compare the efficacy of systemic exposure with individual inflammatory med iators on neutrophil activation and sequestration in the hepatic vasculatur e of C3Heb/FeJ mice as assessed by flow cytometry and histochemistry, respe ctively. The CXC chemokine macrophage inflammatory protein-2 (MIP-2; 20 mug /kg) induced a time-dependent upregulation of Mac-1 (318% at 4 h) and shedd ing of L-selectin (41% at 4 h). MIP-2 treatment caused a temporary increase of sinusoidal neutrophil accumulation at 0.5 h [97 +/- 6 polymorphonuclear leukocytes (PMN)/50 high-power fields (HPF)], which declined to baseline ( 8 +/- 2) at 4 h. The CXC chemokine KC was largely ineffective in activating neutrophils or recruiting them into the liver. Cytokines (tumor necrosis f actor-alpha and interleukin-1 alpha) and cobra venom factor substantially i ncreased Mac-1 expression and L-selectin shedding on neutrophils and caused stable sinusoidal neutrophil accumulation (170-220 PMN/50 HPF). Only cytok ines induced venular neutrophil margination. Thus CXC chemokines in circula tion are less effective than cytokines or complement in activation of neutr ophils and their recruitment into the hepatic vasculature in vivo.