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Tpl2 exaggerated ischemic hepatic injury through induction of apoptosis: Downstream of caspase-9

Douglas H Jacob; Ingrid U Zeng; Yukio Tsung; Shao-Ling Qin; Levi R Blair; Chris A Clarkson; Michael T Braun; Mao Zhao

AJBM  Volume 2, Issue 4, pages 422–439, April 2014             Full Text-PDF


Abstract

Ischemia-reperfusion injury is a dynamic process that involves the two interrelated phases of local ischemic insult and inflammation-mediated reperfusion injury, and an important cause of liver damage occurring during surgical procedures and represents the main underlying cause of graft dysfunction post-transplantation. This study is a highlights into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischemia-reperfusion. Tumor Progression Locus 2 (TPL2) is a serine-threonine kinase with essential functions in innate immune cells, where it transmits signals through Toll-like receptors family. To explore the role of Tpl2 in hepatic injury, liver ischemia/reperfusion injury was induced in wild type mice (Tpl2+/+) and in Tpl2-/- mice. They were sacrificed after 3-days post I/R. We determined TPL2 mRNA levels by quantitative PCR (qPCR), DNA and total RNA extraction from tissues was performed using the DNeasy and miRNeasy Kits, the extents of liver and function were studied. Tpl2 knockout mice produce low levels of proinflammatory cytokines expression, reduced release of LDH, ALT and less hepatic injury than wild type mice when exposed to I/R. Interestingly caspase-3 activation was significantly lower in Tpl2-/- mice. These results suggested that Tpl2 directly involved in apoptotic signal at the level of caspase-3 activation downstream of caspase-9, and that Tpl2 contributed to the exaggerated of ischemic liver injury through induction of apoptosis.

Keywords: Tpl2; Liver I/R; Caspase-3; Caspase-9; Proinflammatory cytokines  


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