title: Reactive nitrogen species-induced cell death requires Fas-dependent activation of c-Jun N-terminal kinase.
abstract: Nitrogen dioxide is a highly toxic reactive nitrogen species (RNS) recently discovered as an inflammatory oxidant with great potential to damage tissues. We demonstrate here that cell death by RNS was caused by c-Jun N-terminal kinase (JNK). Activation of JNK by RNS was density dependent and caused mitochondrial depolarization and nuclear condensation. JNK activation by RNS was abolished in cells lacking functional Fas or following expression of a truncated version of Fas lacking the intracellular death domain. In contrast, RNS induced JNK potently in cells expressing a truncated version of tumor necrosis factor receptor 1 or cells lacking tumor necrosis factor receptor 1 (TNF-R1), illustrating a dependence of Fas but not TNF-R1 in RNS-induced signaling to JNK. Furthermore, Fas was oxidized, redistributed, and colocalized with Fas-associated death domain (FADD) in RNS-exposed cells, illustrating that RNS directly targeted Fas. JNK activation and cell death by RNS occurred in a Fas ligand- and caspase-independent manner. While the activation of JNK by RNS or FasL required FADD, the cysteine-rich domain 1 containing preligand assembly domain required for FasL signaling was not involved in JNK activation by RNS. These findings illustrate that RNS cause cell death in a Fas- and JNK-dependent manner and that this occurs through a pathway distinct from FasL. Thus, avenues aimed at preventing the interaction of RNS with Fas may attenuate tissue damage characteristic of chronic inflammatory diseases that are accompanied by high levels of RNS.
authors.affiliation: Department of Pathology, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405, USA.
authors.forename: Punya
authors.initials: P
authors.lastname: Shrivastava
authors.forename: Cristen
authors.initials: C
authors.lastname: Pantano
authors.forename: Richard
authors.initials: R
authors.lastname: Watkin
authors.forename: Brian
authors.initials: B
authors.lastname: McElhinney
authors.forename: Amy
authors.initials: A
authors.lastname: Guala
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Poynter
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Persinger
authors.forename: Ralph
authors.initials: R
authors.lastname: Budd
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Janssen-Heininger
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D029681:Arabidopsis Proteins / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D004249:DNA Damage; D004789:Enzyme Activation; D047209:Eosinophil Peroxidase; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases / Q000378:metabolism; D007249:Inflammation; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism*; D009585:Nitrogen Dioxide / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010544:Peroxidases / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D026361:Reactive Nitrogen Species; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D029681:Arabidopsis Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D016877:Oxidants; D026361:Reactive Nitrogen Species; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; D030421:Peroxynitrous Acid; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D009584:Nitrogen; D009585:Nitrogen Dioxide; D010100:Oxygen