Minireview Survival of TNF toxicity: Dependence on caspases and NO Anje Cauwels * , Peter Brouckaert Department for Molecular Biomedical Research, VIB, B-9052 Ghent, Belgium Department of Molecular Biology, Ghent University, B-9052 Ghent, Belgium Received 14 December 2006 Available online 8 February 2007 Abstract Tumor necrosis factor (TNF) is an endogenous pro-inflammatory cytokine, implicated in pathologies such as rheumatoid arthritis and septic shock. It was originally discovered as a factor with extraordinary antitumor activity, but its shock-inducing properties still prevent its systemic use in cancer. Clinical trials revealed hypotension as the major dose-limiting factor of TNF toxicity. When admin- istered to mice, TNF provokes a lethal shock syndrome, where cardiovascular collapse is centrally orchestrated by nitric oxide (NO). Nevertheless, NO synthase (NOS) inhibition in animal models and septic shock patients could not improve and even aggravated out- come, suggesting a bivalent role for NO. Lymphocyte and enterocyte apoptosis has been described in septic, endotoxemic, or TNF-treat- ed animals, as well as in septic patients. In this review, we describe our recent studies on the role of NO and caspases in TNF-induced shock in mice. In summary, we have found that both NO and caspases may exert unexpected and dual functions during TNF shock. Whereas excessive NO production provokes lethal hypotension, it also has an important anti-oxidant function, protecting organs from oxidative stress and lipid peroxidation. In addition, our results also indicate that caspases may exert an important endogenous negative feedback on oxidative stress as well. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Tumor necrosis factor; Nitric oxide; Caspases; Reactive oxygen species; Shock; Lipid peroxidation; Anti-oxidant treatments; zVAD-fmk; Phospholipase A2; In vivo; Mice Tumor necrosis factor (TNF) 1 was first molecularly defined in 1984 as a cytokine with exceptional antitumor effects both in vitro and in vivo [1]. Although originally named after its antitumor potential, research over the last decades has shown that TNF is a pleiotropic pro-inflam- matory cytokine, causally involved in many pathologies, including septic shock, inflammatory bowel disease, rheu- matoid arthritis, diabetes, multiple sclerosis and various pulmonary diseases. TNF may elicit its effects by binding to two different receptors, TNF-R1 and TNF-R2 (reviewed in [2]). TNF-R1 is constitutively expressed in most cell types, and numerous experimental approaches have proven that TNF-R1 mediates the majority of the biological effects attributed to TNF [3]. In vitro, TNF has been shown to reg- ulate cell death, proliferation, differentiation and survival [4]. In vivo, TNF causes hepatocyte apoptosis and lethal hepatitis when administered together with transcriptional inhibitors, which may be efficiently prevented by caspase inhibition [5]. When injected without transcriptional inhibitors, TNF causes a lethal shock syndrome [6], as well as early TNF-R1 dependent apoptotic detachment of enterocytes resulting in villus atrophy [7], which may also be prevented by caspase inhibition [8]. 0003-9861/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2007.01.021 * Corresponding author. Department for Molecular Biomedical Re- search, Technologiepark 927, B-9052 Ghent, Belgium. Fax: +32 9 3313609. E-mail address: Anje.Cauwels@dmbr.UGent.be (A. Cauwels). 1 Abbreviations used: TNF, tumor necrosis factor; NO, nitric oxide; NOS, NO synthase; ILP, isolated limb perfusion; CO, carbon monoxide; MB, methylene blue; L-NAME, N G -nitro-L-arginine methyl ester; ROS, reactive oxygen species; SOD, superoxide dismutase; MPT, mitochondrial permeability transition; HNE, 4-hydroxy-2-nonenal; BHA, butylated hydroxyanisole; DPI, diphenyleneiodonium; 3-NP, 3-nitropropionic acid; DD, death domain; TRADD, TNF-R1-associated DD; FADD, Fas- associated DD; RIP1, receptor interacting protein 1; TRAF2, TNFR- associated factor 2; mTNF, mouse TNF; hTNF, human TNF; IKK, IjB kinase; ANT, adenine nucleotide translocase; AA, arachidonic acid; P13K, phosphoinositide 3-kinase; PLA2, phospholipase A2; sGC, soluble guanylate cyclase. www.elsevier.com/locate/yabbi Archives of Biochemistry and Biophysics 462 (2007) 132–139 ABB