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Toxicologic Pathology
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Protective Effect of rhIL-11 in a Murine Model of Acetaminophen-Induced Hepatotoxicity

William L. Trepicchio

Department of Molecular Medicine, Genetics Institute/ Wyeth Research, Andover, Massachusetts 01810

Mary Bozza

Department of Molecular Medicine, Genetics Institute/ Wyeth Research, Andover, Massachusetts 01810

Page Bouchard

Department of Drug Safety and Metabolism, Genetics Institute/ Wyeth Research, Andover, Massachusetts 01810

Andrew J. Dorner

Department of Molecular Medicine, Genetics Institute/ Wyeth Research, Andover, Massachusetts 01810, ajdorner{at}genetics.com

Acetaminophen intoxication results in hepatotoxicity associated with increased serum concentrations of hepatocellular leakage enzymes such as aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase, centrilobular degeneration and necrosis, and activation of Kupffer cells. Recombinant human Interleukin-11 (rhIL-11) downregulates the production of proinfl ammatory mediators from activated macrophages and has direct effects on hepatocyte gene expression. Based on these biological activities of rhIL-11, the effect of pretreatment with rhIL-11 in a murine model of acetaminophen-induce d hepatotoxicity was examined. Administration of 500 ug/kg acetaminophen to B6C3F1 mice resulted in progressive hepatotoxicity as demonstrated by elevated serum concentration s of hepatocellular leakage enzymes and TNF{alpha} and histopathology. Pretreatment with 250 or 500 ug/kg of subcutaneously administered rhIL-11 2 hours before acetaminophen administration reduced serum concentrations of hepatocellular leakage enzyme s and TNF{alpha} by 40—50%. This was associated with a statistically significant decreas e in mean severity score for centrilobular hemorrhag e and necrosis from grade 3 to grade 2 for rhIL-11-treated animals compared to vehicle. These results indicate that treatment with rhIL-11 has a protective effect in a model of acetaminophen-induce d liver damage.

Key Words: Acetaminophen • cytokine • inflammation • interleukin-11 • liver damage.

Toxicologic Pathology, Vol. 29, No. 2, 242-249 (2001)
DOI: 10.1080/019262301317052521
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 Toxicol PatholHome page
G. M. Williams and M. J. Iatropoulos
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Toxicol Pathol, January 1, 2002; 30(1): 41 - 53.
[Abstract] [PDF]