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Am J Physiol Gastrointest Liver Physiol 281: G654-G665, 2001;
0193-1857/01 $5.00
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Vol. 281, Issue 3, G654-G665, September 2001

NO-mesalamine protects colonic epithelial cells against apoptotic damage induced by proinflammatory cytokines

Stefano Fiorucci1, Eleonora Distrutti1, Maureen N. Ajuebor2, Andrea Mencarelli1, Roberta Mannucci3, Barbara Palazzetti1, Piero Del Soldato4, Antonio Morelli1, and John L. Wallace2

1 Clinica di Gastroenterologia ed Epatologia and 3 Sezione di Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, 06100 Perugia, Italy; 2 Mucosal Inflammation Research Group, University of Calgary, Calgary T2N 4N1, Alberta, Canada; and 4 Nicox, Sophia Antipolis 06906, France

The activation of a self-amplifying cascade of caspases, of which caspase-8 is the apical protease, mediates Fas-, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-, and TNF-alpha -induced apoptosis in colon cell lines. Nitric oxide (NO) protects from apoptosis induced by Fas and TNF-alpha . We examined whether NCX-456, an NO-releasing derivative of mesalamine, protects colon epithelial cells from cytokine-induced apoptosis. Caco-2 and HT-29 cell lines express death factor receptors and are driven to apoptosis in response to incubation with Fas-agonistic antibody, TNF-alpha /interferon-gamma , and TRAIL. The two novel observations reported here are that 1) cotreatment of cells with NCX-456, but not mesalamine, resulted in concentration-dependent protection against death factor-induced apoptosis and inhibition of caspase activity, and 2) exposure to dithiothreitol, an agent that effectively removes NO from thiol groups, resulted in a 70% recovery of caspase activity, which is consistent with S-nitrosation as a major mechanism for caspase inactivation. These data suggest that caspase S-nitrosation represents a mechanism for protection of colonic mucosal epithelial cells from death factor-induced death.

colon cancer cells; apoptosis; death factors; nitromesalamine


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