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

Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G654-65. doi: 10.1152/ajpgi.2001.281.3.G654.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Aminosalicylic Acids / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects*
  • Caco-2 Cells
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / biosynthesis
  • Caspases / genetics
  • Colon / cytology
  • Colon / drug effects*
  • Colon / metabolism
  • Cytokines / antagonists & inhibitors*
  • Cytokines / toxicity
  • Cytoprotection
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • GPI-Linked Proteins
  • HT29 Cells
  • Humans
  • Interferon-gamma / pharmacology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Mesalamine / pharmacology
  • Nitric Oxide / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor, Member 10c
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Aminosalicylic Acids
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies, Monoclonal
  • Caspase Inhibitors
  • Cytokines
  • Enzyme Inhibitors
  • GPI-Linked Proteins
  • NO-mesalamine
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Member 10c
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFRSF10C protein, human
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Nitric Oxide
  • Mesalamine
  • Interferon-gamma
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases