Adenovirus-mediated expression of CINC/GRO (IL-8) in rat liver induces a neutrophilic hepatitis

J. I. Maher, M. K. Scott, J. M. Saito, Mc Burton

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Interleukin-8 (IL-8) is a C-χ-C chemokine with potent chemotactic activity toward neutrophils. IL-8 circulates in large amounts in patients with neutrophilic hepatitis; although produced by liver cells, it has not been proven directly to cause neutrophil migration to the liver. The objective of this study was to determine the pathogenic potential of liver-derived IL-8 by overexpressing its rat analogue CINC/gro in rat liver via adeno virus-media ted gene delivery. Methods: A 291-bp cDNA encoding CINC/gro was cloned and inserted into an ElA-deleted Ad5 expression vector. Cotransfection of the resulting plasmid into 293 cells with pJM17 yielded a replication-defective recombinant adenovirus (Ad5-CMV-CINC). The virus was administered to intact rats via portal vein injection, after which the animals were monitored for CINC expression and for signs of liver injury. Results: Rats infected with Ad5CMV-C1NC exhibited a dose-dependent increase in CINC expression at 4 days. Virus-infected rats exhibited higher levels of liver and plasma CINC {liver, 106.4 vs 6.3 pg/mg protein; plasma, 527 vs 142 pg/ml) and larger numbers of circulating neutrophils (8.3 vs 0.9 K/μl) than did uninfected rats. Hepatic transaminases and bilirubin were also markedly increased (AST, 990 vs 134 IU/L; Bili, 1.6 vs 0.1 mg/dl). Histology revealed a severe hepatitis with hepatocytes surrounded by neutrophils. Control rats infected with Ad5 without CINC exhibited some neutrophilia, but little biochemical or histologie liver damage. Summary: CINC/gro, when produced in sufficient quantity by rat liver cells, induces a neutrophilic hepatitis. Conclusion: hi humans, liverderived IL-8 is a likely cause of neutrophilic hepatitis. (AA07810/ABMRF).

Original languageEnglish
Pages (from-to)A1003
JournalFASEB Journal
Issue number6
StatePublished - Dec 1 1996


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