Survival of TNF toxicity: dependence on caspases and NO.
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 administered 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 outcome, suggesting a bivalent role for NO. Lymphocyte and enterocyte apoptosis has been described in septic, endotoxemic, or TNF-treated 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.
Cauwels
Anje
A
Department for Molecular Biomedical Research, VIB, B-9052 Ghent, Belgium. Anje.Cauwels@dmbr.UGent.be
Brouckaert
Peter
P
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000633:toxicity*
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D048069:Tumor Necrosis Factors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020169:Caspases