Dichotomy between RIP1- and RIP3-Mediated Necroptosis in Tumor Necrosis Factor-alpha-Induced Shock

Linkermann, Andreas, Braesen, Jan H., De Zen, Federica, Weinlich, Ricardo, Schwendener, Reto A., Green, Douglas R., Kunzendorf, Ulrich and Krautwald, Stefan (2012) Dichotomy between RIP1- and RIP3-Mediated Necroptosis in Tumor Necrosis Factor-alpha-Induced Shock Molecular Medicine, 18 (4). pp. 577-586.

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Abstract

Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNF alpha-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNF alpha-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNF alpha/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP), we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis. Online address: hitp://www.molmed.org doi: 10.2119/molmed.2011.00423

Document Type: Article
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
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ISSN: 1076-1551
Projects: Future Ocean
Date Deposited: 14 May 2014 09:51
Last Modified: 14 May 2014 09:51
URI: http://eprints.uni-kiel.de/id/eprint/24098

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