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Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO‐1 dependence of Stat4 disruption‐mediated cytoprotection

Ischemia/reperfusion (I/R) injury remains an important problem in clinical organ transplantation. There is growing evidence that T lymphocytes, and activated CD4+ T cells in particular, play a key role in hepatic I/R injury. This study analyzes the role of signal transducer and activator of transcription 4 (Stat4) and Stat6 signaling in liver I/R injury. Using a partial lobar warm ischemia model, groups of wild‐type (WT), T cell–deficient, Stat4‐/Stat6‐deficient knockout (KO) mice were assessed for the extent/severity of I/R injury. Ninety minutes of warm ischemia followed by 6 hours of reperfusion induced a fulminant liver failure in WT and Stat6 KO mice, as assessed by hepatocellular damage (serum alanine aminotransferase [sALT] levels), neutrophil accumulation (myeloperoxidase [MPO] activity) and histology (Suzuki scores). In contrast, T cell deficiency (nu/nu mice) or disruption of Stat4 signaling (Stat4 KO mice) reduced I/R insult. Unlike adoptive transfer of WT or Stat6‐deficient T cells, infusion of Stat4‐deficient T cells failed to restore hepatic I/R injury and prevented tumor necrosis factor α (TNF‐α) production in nu/nu mice. Diminished TNF‐α/Th1‐type cytokine messenger RNA (mRNA)/protein elaborations patterns, along with overexpression of heme oxygenase‐1 (HO‐1)–accompanied hepatic cytoprotection in Stat4 KO recipients. In contrast, HO‐1 depression restored hepatic injury in otherwise I/R resistant Stat4 KOs. In conclusion, Stat4 signaling is required for, whereas Stat4 disruption protects against, warm hepatic I/R injury in mice. The cytoprotection rendered by Stat4 disruption remains HO‐1–dependent.