Activation of nuclear factor-κB and transcription of adhesion molecule genes in the liver during endotoxin shock

Intercellular adhesion molecule-1 (ICAM-1) and beta(2) integrins are critical for neutrophil-induced liver injury during endotoxin shock. The objective of this investigation was to study the role of vascular adhesion molecule-1 (VCAM-1) and P-selectin in the pathophysiology. Male C3Heb/FeJ mice were treated with 700 mg/kg galactosamine, 100 mu g/kg endotoxin or a combination of both. In all endotoxin-treated animals, a massive activation of the transcription factor NF-KB was observed in the liver and consequently mRNA formation of the NF-kappa B-dependent genes VCAM-1 and P-selectin increased significantly. A similar treatment in C3H/HeJ mice (endotoxin-resistant strain), which do not generate cytokines in response to endotoxin, did not result in NF-kappa B activation or transcriptional upregulation of VCAM-1 or P-selectin. However, injection of TNF-alpha or IL-1 increased VCAM-1 and P-selectin mRNA levels in both strains of mice. The severe liver injury observed at 7 h after administration of galactosamine/endotoxin was not affected by pretreatment with an antibody to P-selectin or isotype-matched IgG. In contrast, an antibody to VCAM-1 attenuated plasma ALT levels by 90% and the area of necrosis by 60%. Neither the antibody to P-selectin nor VCAM-1 reduced the number of neutrophils accumulated in the liver. Our data suggest that NF-kappa(B) activation and adhesion molecule gene regulation in the liver in vivo is mediated by TNF-alpha and IL-1. Furthermore, neutrophils may use very late antigen-4/VCAM-1 interactions in addition to beta(2) integrin/ICAM-1 for extravasation and parenchymal cell injury in the liver.