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

Authors
  • Fiorucci, S
  • Distrutti, E
  • Ajuebor, M N
  • Mencarelli, A
  • Mannucci, R
  • Palazzetti, B
  • Del Soldato, P
  • Morelli, A
  • Wallace, J L
Type
Published Article
Journal
American journal of physiology. Gastrointestinal and liver physiology
Publication Date
Sep 01, 2001
Volume
281
Issue
3
Identifiers
PMID: 11518677
Source
Medline
License
Unknown

Abstract

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.

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