Abstract
Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ALT:
-
alanine aminotransferase
- AST:
-
aspartate aminotransferase
- Con A:
-
concanavalin A
- GA:
-
geldanamycin
- MEFs:
-
mouse embryonic fibroblasts
- NAC:
-
N-acetyl-cysteine
- Nec-1:
-
necrostatin-1
- NKT:
-
natural killer T
- PAR:
-
poly ADP ribosylation
- PARP-1:
-
poly (ADP-ribose) polymerase-1
- pHe:
-
extracellular pH
- RIPK1/3:
-
receptor interacting protein kinase 1/3
- ROS:
-
reactive oxygen species
- TNF:
-
tumor necrosis factor
- TRAIL:
-
TNF-related apoptosis inducing ligand
References
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155–162.
Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7: 94–100.
Zheng SJ, Wang P, Tsabary G, Chen YH . Critical roles of TRAIL in hepatic cell death and hepatic inflammation. J Clin Invest 2004; 113: 58–64.
Gonzalvez F, Ashkenazi A . New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010; 29: 4752–4765.
Wu GS, Burns TF, Zhan Y, Alnemri ES, El-Deiry WS . Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res 1999; 59: 2770–2775.
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489–495.
Kemp TJ, Kim JS, Crist SA, Griffith TS . Induction of necrotic tumor cell death by TRAIL/Apo-2L. Apoptosis 2003; 8: 587–599.
Meurette O, Huc L, Rebillard A, Le Moigne G, Lagadic-Gossmann D, Dimanche-Boitrel MT . TRAIL (TNF-related apoptosis-inducing ligand) induces necrosis-like cell death in tumor cells at acidic extracellular pH. Ann NY Acad Sci 2005; 1056: 379–387.
Meurette O, Rebillard A, Huc L, Le Moigne G, Merino D, Micheau O et al. TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions. Cancer Res 2007; 67: 218–226.
Lardner A . The effects of extracellular pH on immune function. J Leukoc Biol 2001; 69: 522–530.
Wike-Hooley JL, van den Berg AP, van der Zee J, Reinhold HS . Human tumour pH and its variation. Eur J Cancer Clin Oncol 1985; 21: 785–791.
Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA . AIF-mediated programmed necrosis: a highly regulated way to die. Cell Cycle 2007; 6: 2612–2619.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1: 112–119.
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G . Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010; 11: 700–714.
Andrabi SA, Dawson TM, Dawson VL . Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann NY Acad Sci 2008; 1147: 233–241.
Degterev A, Yuan J . Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 2008; 9: 378–390.
Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009; 137: 1112–1123.
He S, Wang L, Miao L, Wang T, Du F, Zhao L et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137: 1100–1111.
Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325: 332–336.
Tiegs G, Gantner F . Immunotoxicology of T cell-dependent experimental liver injury. Exp Toxicol Pathol 1996; 48: 471–476.
Kaneko Y, Harada M, Kawano T, Yamashita M, Shibata Y, Gejyo F et al. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med 2000; 191: 105–114.
Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K . Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA 2000; 97: 5498–5503.
Toyabe S, Seki S, Iiai T, Takeda K, Shirai K, Watanabe H et al. Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. J Immunol 1997; 159: 1537–1542.
Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W . Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992; 267: 5317–5323.
Goossens V, De Vos K, Vercammen D, Steemans M, Vancompernolle K, Fiers W et al. Redox regulation of TNF signaling. Biofactors 1999; 10: 145–156.
Jan G, Belzacq AS, Haouzi D, Rouault A, Métivier D, Kroemer G et al. Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria. Cell Death Differ 2002; 9: 179–188.
Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4: 313–321.
Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135: 1311–1323.
Festjens N, Vanden Berghe T, Vandenabeele P . Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757: 1371–1387.
Temkin V, Huang Q, Liu H, Osada H, Pope RM . Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol Cell Biol 2006; 26: 2215–2225.
Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A et al. Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol Biol Cell 2002; 13: 978–988.
Wang Y, Dawson VL, Dawson TM . Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 2009; 218: 193–202.
Vanden Berghe T, Kalai M, van Loo G, Declercq W, Vandenabeele P . Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis. J Biol Chem 2003; 278: 5622–5629.
Xu Y, Huang S, Liu ZG, Han J . Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 2006; 281: 8788–8795.
Gagne JP, Moreel X, Gagne P, Labelle Y, Droit A, Chevalier-Paré M et al. Proteomic investigation of phosphorylation sites in poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase. J Proteome Res 2009; 8: 1014–1029.
Christofferson DE, Yuan J . Cyclophilin A release as a biomarker of necrotic cell death. Cell Death Differ 2010; 17: 1942–1943.
Scaffidi P, Misteli T, Bianchi ME . Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191–195.
Sass G, Heinlein S, Agli A, Bang R, Schümann J, Tiegs G . Cytokine expression in three mouse models of experimental hepatitis. Cytokine 2002; 19: 115–120.
Hu X, Han W, Li L . Targeting the weak point of cancer by induction of necroptosis. Autophagy 2007; 3: 490–492.
Lepretre C, Scovassi AI, Shah GM, Torriglia A . Regulation of poly(ADP-ribose) polymerase-1 functions by leukocyte elastase inhibitor/LEI-derived DNase II during caspase-independent apoptosis. Int J Biochem Cell Biol 2009; 41: 1046–1054.
Acknowledgements
We are grateful to Dr. Alicia Torriglia and Dr. Mathieu Bertrand for helpful discussions. We thank in particular Linde Duprez and Mathieu Bertrand for preparing and making available ripk1 and ripk3 knockout MEF cells. We also thank the animal house facilities, the flow cytometry platform and the immunohistology platform (SFR Biosit, Rennes). Research in the IRSET group was supported by grants from the Ligue Nationale Contre le Cancer (the Côte d’Armor, Ille et Vilaine, Morbihan, Vendée and Sarthe Comittees), INSERM, University of Rennes 1 and the Region Bretagne. S Jouan-Lanhouet was supported by the Association pour la Recherche sur le Cancer (doctoral fellowship). Research in the Vandenabeele group has been supported by Flanders Institute for Biotechnology (VIB), by European grants (FP6 ApopTrain, MRTN-CT-035624; FP7 EC RTD Integrated Project, Apo-Sys, FP7–200767; Euregional PACT II), Belgian grants (Interuniversity Attraction Poles, IAP 6/18), Flemish grants (Fonds Wetenschappelijk Onderzoek Vlaanderen, FWO G.0875.11 and FWO G.0973.11) and Ghent University grants (MRP, GROUP-ID). P Vandenabeele is also holder of a Methusalem grant (BOF09/01M00709) from the Flemish Government.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by C Borner
Supplementary Information accompanies the paper on Cell Death and Differentiation website
Supplementary information
Rights and permissions
About this article
Cite this article
Jouan-Lanhouet, S., Arshad, M., Piquet-Pellorce, C. et al. TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ 19, 2003–2014 (2012). https://doi.org/10.1038/cdd.2012.90
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cdd.2012.90
Keywords
This article is cited by
-
The importance of murine phospho-MLKL-S345 in situ detection for necroptosis assessment in vivo
Cell Death & Differentiation (2024)
-
AATF Competitively Interacts with Nuclear AIF and Inhibits Parthanatos of Neurons in dMCAO/R and OGD/R Models
Journal of Molecular Neuroscience (2022)
-
The regulation of necroptosis by ubiquitylation
Apoptosis (2022)
-
The molecular mechanism of acute liver injury and inflammatory response induced by Concanavalin A
Molecular Biomedicine (2021)
-
Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor
Cell Death & Disease (2021)
