Abstract
Tumor necrosis factor-alpha (TNFalpha)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of pro-death Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNFalpha-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNFalpha in the presence of d-galactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the bid-deficient mice. Additional genetic factor(s) could further modify the dependence of TNFalpha toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNFalpha-mediated pathogenesis in vivo.
Highlights
Are due to a series of cytokine reactions, TNF␣ can exert direct cytotoxic effects on the cell (8 –11)
Since Bid, a “BH3-only” pro-death Bcl-2 family protein can be proteolytically activated by caspase 8 in response to death receptor activation, leading to Bid translocation to mitochondria and cytochrome c release [32, 38, 39], we hypothesized that the Bid-initiated mitochondria apoptosis pathway could contribute to the in vivo TNF␣ cytotoxicity, such as hepatic injury
LPS and D-Galactosamine Induce Bid Cleavage and Cytochrome c Release in Murine Hepatocytes—One of the most common approaches to induce TNF␣-mediated liver damage in mice is to administer a low dose of LPS in the presence of a liver-specific transcription inhibitor, GalN, that results in massive hepatocyte apoptosis [12,13,14, 16, 17, 19, 40]
Summary
Are due to a series of cytokine reactions, TNF␣ can exert direct cytotoxic effects on the cell (8 –11). Since Bid, a “BH3-only” pro-death Bcl-2 family protein can be proteolytically activated by caspase 8 in response to death receptor activation, leading to Bid translocation to mitochondria and cytochrome c release [32, 38, 39], we hypothesized that the Bid-initiated mitochondria apoptosis pathway could contribute to the in vivo TNF␣ cytotoxicity, such as hepatic injury. Activation of Bid seemed to be responsible for the release of cytochrome c and the activation of mitochondria-initiated caspase cascade Both effector caspase activation and liver damage were significantly retarded, not eliminated, in the absence of Bid. On the other hand, the deletion of the Bax did not seem to significantly affect the mitochondrial release of cytochrome c and caspase activation, suggesting that Bax was not the only molecule that could mediate the activity of Bid. a recent study showed that Bid could activate another pro-death Bcl-2 family protein, Bak, by inducing its oligomerization [42], suggesting that Bak could serve as yet another downstream target of Bid. multiple pro-death Bcl-2 family proteins, led by Bid, could be sequentially activated in vivo to trigger the mitochondria apoptotic pathway. We concluded that prodeath Bcl-2 family proteins and the mitochondria apoptosis pathway played a critical role in the early development of TNF␣-induced hepatocyte apoptosis and pathogenesis in vivo
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call