351. Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice
- Author
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Dan Takeuchi, Hiroshi Ito, Masaru Miyazaki, Masayuki Ohtsuka, Hiroaki Shimizu, Yasuhiro Morita, Fumio Kimura, Hiroyuki Yoshidome, and Atsushi Kato
- Subjects
Male ,Ischemia ,Apoptosis ,Pharmacology ,Mice ,Medicine ,Animals ,Interleukin 4 ,Liver injury ,TUNEL assay ,Hepatology ,biology ,business.industry ,Interleukin-18 ,NF-kappa B ,medicine.disease ,Interleukin-10 ,Mice, Inbred C57BL ,Transcription Factor AP-1 ,Interleukin 10 ,Liver ,Neutrophil Infiltration ,Myeloperoxidase ,Chemokines, CC ,Reperfusion Injury ,Immunology ,biology.protein ,Trans-Activators ,Interleukin 18 ,Interleukin-4 ,business ,STAT6 Transcription Factor ,Reperfusion injury ,Chemokines, CXC ,Liver Circulation - Abstract
Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-kappaB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.
- Published
- 2004