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 micrograms/kg Salmonella abortus equi endotoxin (ET) in galactosamine-sensitized mice (Gal). In ET-sensitive mice (C3Heb/FeJ), which generated large amounts of tumor necrosis factor-alpha (TNF-alpha), massive neutrophil infiltration and severe liver injury were observed. In an ET-resistant strain (C3H/HeJ), which did not generate TNF-alpha 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-alpha, interleukin-1 alpha (IL-1 alpha) or IL-I beta (13 to 23 micrograms/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-alpha 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-alpha 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. (ABSTRACT TRUNCATED AT 250 WORDS)
Essani
N A
NA
Upjohn Company, Kalamazoo, MI 49001, USA.
Fisher
M A
MA
Farhood
A
A
Manning
A M
AM
Smith
C W
CW
Jaeschke
H
H
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D004731:Endotoxins / Q000633:toxicity; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017114:Liver Failure, Acute / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012475:Salmonella; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology*; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D017931:DNA Primers; D004731:Endotoxins; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1