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

Authors

  • Xiu-Da Shen,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Bibo Ke,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Yuan Zhai,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Feng Gao,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Dean Anselmo,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Charles R. Lassman,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Ronald W. Busuttil,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
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  • Jerzy W. Kupiec-Weglinski 10833 Le Conte Ave.

    Corresponding author
    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, and Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA
    • Los Angeles, CA 90095; fax: 310-267-2358
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Abstract

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.

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