title: TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death.
abstract: Programmed necrosis is important in many (patho)physiological settings. For specific therapeutic intervention, however, a better knowledge is required whether necrosis occurs through one single "core program" or through several independent pathways. Previously, the poly(ADP-ribose) polymerase (PARP) pathway has been suggested as a crucial element of tumor necrosis factor (TNF)-mediated necroptosis. Here, we show that TNF-induced necroptosis and the PARP pathway represent distinct and independent routes to programmed necrosis. First, DNA-alkylating agents such as 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) or methyl methanesulfonate rapidly activate the PARP pathway, whereas this is a late and secondary event in TNF-induced necroptosis. Second, inhibition of the PARP pathway does not protect against TNF-induced necroptosis, e.g., the PARP-1 inhibitor 3-AB prevented MNNG- but not TNF-induced adenosine-5'-triposphate depletion, translocation of apoptosis-inducing factor, and necrosis. Likewise, olaparib, a more potent and selective PARP-1 inhibitor failed to block TNF-induced necroptosis, identical to knockdown/knockout of PARP-1, pharmacologic and genetic interference with c-Jun N-terminal kinases and calpain/cathepsin proteases as further components of the PARP pathway. Third, interruption of TNF-induced necroptosis by interference with ceramide generation, RIP1 or RIP3 function or by the radical scavenger butylated hydroxyanisole did not prevent programmed necrosis through the PARP pathway. In summary, our results suggest that the currently established role of the PARP pathway in TNF-induced necroptosis needs to be revised, with consequences for the design of future therapeutic strategies.
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Michaelisstr. 5, 24105, Kiel, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sosna
authors.forename: Susann
authors.initials: S
authors.lastname: Voigt
authors.forename: Sabine
authors.initials: S
authors.lastname: Mathieu
authors.forename: Arne
authors.initials: A
authors.lastname: Lange
authors.forename: Lutz
authors.initials: L
authors.lastname: Thon
authors.forename: Parvin
authors.initials: P
authors.lastname: Davarnia
authors.forename: Thomas
authors.initials: T
authors.lastname: Herdegen
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D061986:MCF-7 Cells; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D009336:Necrosis; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C119724:AGFG1 protein, human; D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D002518:Ceramides; D016166:Free Radical Scavengers; D006146:Guanidines; D028861:Nuclear Pore Complex Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C082988:N-methyl-N'-nitroguanidine; C025160:3-aminobenzamide; D008741:Methyl Methanesulfonate; D011065:Poly(ADP-ribose) Polymerases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D002403:Cathepsins; D002154:Calpain; C531550:olaparib