Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure
Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecule Mac-1 (CD11b/CD18) on neutrophils. The potential involvement of its counterreceptor, intercellular adhesion molecule-1 (ICAM-1), in the pathogenesis was investigated after administration of 100 μg/kg Salmonella abortus equi endotoxin (ET) in galactosamine-sensitized mice (Gal). In ETsensitive mice (C3Heb/FeJ), which generated large amounts of tumor necrosis factor-alpha (TNF-α), massive neutrophil infiltration and severe liver injury were observed. In an ET-resistant strain (C3H/HeJ), which did not generate TNF-α, Gal/ET failed to cause neutrophil accumulation or injury. ICAM-1 messenger RNA (mRNA), negligible in control livers, was selectively induced by Gal/ET in ET-sensitive mice. Intravenous injection of murine TNF-α, interleukin-1 alpha (IL-1α) or IL-1β (13 to 23 μg/kg) strongly induced the ICAM-1 message in both strains, showing a comparable capacity for ICAM-1 mRNA synthesis. All cytokines caused similar neutrophil accumulation in the liver; however, only Gal/ TNF-α also caused upregulation of Mac-1 on circulating neutrophils and liver injury. The anti-murine ICAM-1 monoclonal antibody YN.1 (3 mg/kg) attenuated liver injury in ET-sensitive mice by 67% to 90% compared with isotype-matched control antibody-treated animals but did not reduce neutrophil accumulation in hepatic sinusoids. Our data suggest that the cytokines TNF-α and IL-1 are the main mediators responsible for upregulation of ICAM-1 mRNA in the liver during endotoxemia. The upregulation of both adhesion molecules, ICAM-1 and Mac-1, is necessary for a neutrophil-induced liver injury to occur. Blocking ICAM-1 and/or interfering with ICAM1 induction could be a successful therapeutic strategy to prevent sepsis-related inflammatory liver injury. © 1995.
Essani, N., Fisher, M., Farhood, A., Manning, A., Smith, C., & Jaeschke, H. (1995). Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology, 21 (6). http://dx.doi.org/10.1016/0270-9139(95)90469-7