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 mediators on neutrophil activation and sequestration in the hepatic vasculature of C3Heb/FeJ mice as assessed by flow cytometry and histochemistry, respectively. The CXC chemokine macrophage inflammatory protein-2 (MIP-2; 20 microg/kg) induced a time-dependent upregulation of Mac-1 (318% at 4 h) and shedding 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 factor-alpha and interleukin-1alpha) and cobra venom factor substantially increased Mac-1 expression and L-selectin shedding on neutrophils and caused stable sinusoidal neutrophil accumulation (170-220 PMN/50 HPF). Only cytokines induced venular neutrophil margination. Thus CXC chemokines in circulation are less effective than cytokines or complement in activation of neutrophils and their recruitment into the hepatic vasculature in vivo.
Bajt
M L
ML
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Farhood
A
A
Jaeschke
H
H
D000818:Animals; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003165:Complement System Proteins / Q000494:pharmacology; D006133:Growth Substances / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018375:Neutrophil Activation / Q000187:drug effects*; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003165:Complement System Proteins