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Molecular and Cellular Biology, August 2004, p. 6763-6772, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6763-6772.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Reactive Nitrogen Species-Induced Cell Death Requires Fas-Dependent Activation of c-Jun N-Terminal Kinase

Punya Shrivastava,1 Cristen Pantano,1,{dagger} Richard Watkin,1,{dagger} Brian McElhinney,1,{dagger} Amy Guala,1 Matthew L. Poynter,1 Rebecca L. Persinger,1 Ralph Budd,2,{dagger} and Yvonne Janssen-Heininger1*

Departments of Pathology,1 Medicine, University of Vermont, Burlington, Vermont 054052

Received 16 April 2004/ Accepted 13 May 2004

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.

* Corresponding author. Mailing address: Department of Pathology, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Phone: (802) 656-0995. Fax: (802) 656-8892. E-mail: yvonne.janssen{at}uvm.edu.

{dagger} C.P., R.W., and B.M. contributed equally to this work.

Molecular and Cellular Biology, August 2004, p. 6763-6772, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6763-6772.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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