Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice.
Hepatic ischemia and reperfusion causes neutrophil-dependent liver injury. Although the mechanisms of ischemia/reperfusion-induced liver neutrophil recruitment are somewhat understood, less is known regarding the early events that initiate the inflammatory injury. Using a murine model of partial hepatic ischemia and reperfusion, we evaluated the role of endogenous interleukin (IL)-12 in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion for up to 4 hours resulted in hepatocyte expression of IL-12. By 8 hours of reperfusion there were large increases in serum levels of interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha). In addition, hepatic ischemia/reperfusion caused significant increases in liver neutrophil recruitment, hepatocellular injury, and liver edema, as defined by liver myeloperoxidase content, serum alanine aminotransferase, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL-12 and in mice deficient in the IL-12 p40 gene, ischemia/reperfusion-induced increases in IFNgamma and TNFalpha were greatly diminished. These conditions also caused significant reductions in liver myeloperoxidase content and attenuated the parameters of liver injury. The data suggest that IL-12 is required for the full induction of injury after hepatic ischemia and reperfusion.
Lentsch
A B
AB
Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA. alentsch@louisville.edu
Yoshidome
H
H
Kato
A
A
Warner
R L
RL
Cheadle
W G
WG
Ward
P A
PA
Edwards
M J
MJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies; D016207:Cytokines / Q000097:blood*; D017353:Gene Deletion; D006358:Hot Temperature; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008107:Liver Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation
D000906:Antibodies; D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D000410:Alanine Transaminase