Promotion of hepatic ischemia/reperfusion injury by IL-12 is independent of STAT4.

摘要

BACKGROUND: We have recently demonstrated a role for interleukin-12 (IL-12) in the induction and development of hepatic ischemia/reperfusion injury. IL-12 mediates its effects through the transcription factor, signal transducer and activator of transcription-4 (STAT4). Therefore, we investigated the response to hepatic ischemia/reperfusion in STAT4-deficient mice. METHODS: Wild-type and STAT4-deficient mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion. In some experiments, IL-12 was neutralized with antibody administered intravenously. RESULTS: Wild-type mice demonstrated rapid activation of STAT4 in liver after ischemia/reperfusion, which mirrored hepatic protein expression of IL-12. Interestingly, STAT4-deficient mice were indistinguishable from wild-type mice in their response to hepatic ischemia reperfusion. No differences were observed in serum levels of tumor necrosis factor alpha (TNF-alpha), liver accumulation of neutrophils, or hepatocellular injury. However, blockade of endogenous IL-12 significantly reduced these parameters in STAT4-knockout mice. CONCLUSIONS: These data demonstrate that IL-12 promotes hepatic inflammation in a manner that is independent of STAT4 and implicate a novel mechanism for the pro-inflammatory effects of IL-12.