Promotion of hepatic ischemia/reperfusion injury by IL-12 is independent of STAT4.
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.
Kato
Atsushi
A
Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Graul-Layman
Amanda
A
Edwards
Michael J
MJ
Lentsch
Alex B
AB
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015427:Reperfusion Injury / Q000209:etiology*; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D004247:DNA; D000410:Alanine Transaminase