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(American Journal of Pathology. 2000;157:297-302.)
© 2000 American Society for Investigative Pathology

Regular Articles

Regulation of Liver Inflammatory Injury by Signal Transducer and Activator of Transcription-6

Atsushi Kato, Hiroyuki Yoshidome, Michael J. Edwards and Alex B. Lentsch

From the Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky

Liver injury induced by hepatic ischemia/reperfusion is characterized by activation of the transcription factor NF-{kappa}B, increased production of tumor necrosis factor-{alpha} (TNF{alpha}), liver neutrophil accumulation, and hepatocellular damage. Exogenous administration of interleukin-4 (IL-4) or IL-13 was recently shown to regulate this inflammatory injury in association with activation of signal transducer and activator of transcription-6 (STAT6). The objective of the present study was to determine whether STAT6 was required for the regulation of liver inflammation by IL-4 and IL-13. Wild-type and STAT6 knockout mice underwent 90 minutes of hepatic ischemia followed by 8 hours of reperfusion. Hepatic ischemia/reperfusion in wild-type and STAT6 knockout mice significantly increased (P < 0.05) NF-{kappa}B activation, serum levels of TNF{alpha}, liver accumulation of neutrophils [measured by myeloperoxidase (MPO) content], and hepatocellular damage [measured by serum alanine aminotransferase (ALT)] compared to sham controls. In wild-type mice, activation of STAT6 was not observed after ischemia/reperfusion. Administration of 1 µg of IL-4 or IL-13 at reperfusion reduced serum TNF{alpha}, liver neutrophil accumulation, and hepatocellular injury in wild-type mice. Treatment with IL-4 or IL-13 had no effect on liver NF-{kappa}B activation but significantly increased activation of STAT6. In STAT6 knockout mice, neither IL-4 nor IL-13 had any effect on TNF{alpha}, MPO, or ALT values, the regulatory effects of these cytokines being completely abolished. The data suggest that activation of STAT6 may regulate liver inflammatory injury.




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