TY - JOUR
T1 - Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice
T2 - HO-1 dependence of Stat4 disruption-mediated cytoprotection
AU - Shen, Xiu Da
AU - Ke, Bibo
AU - Zhai, Yuan
AU - Gao, Feng
AU - Anselmo, Dean
AU - Lassman, Charles R.
AU - Busuttil, Ronald W.
AU - Kupiec-Weglinski, Jerzy W.
N1 - Funding Information:
Supported by NIH Grants RO1 AI42223, RO1 AI23847, and RO1 DK062357 (JWK-W) and by The Dumont Research Foundation. X-DS and BK are recipients of 2002 American Society of Transplantation (AST) Young Investigator Awards. YZ is the recipient of 2001 American Society of Transplant Surgeons (ASTS) Collaborative Scientist Research Award.
PY - 2003/2/1
Y1 - 2003/2/1
N2 - 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 knock-out (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.
AB - 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 knock-out (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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U2 - 10.1053/jhep.2003.50066
DO - 10.1053/jhep.2003.50066
M3 - Article
C2 - 12540779
AN - SCOPUS:0037308148
SN - 0270-9139
VL - 37
SP - 296
EP - 303
JO - Hepatology
JF - Hepatology
IS - 2
ER -