Induction by activated macrophage-like THP-1 cells of apoptotic and necrotic cell death in intestinal epithelial Caco-2 monolayers via tumor necrosis factor-alpha

Exp Cell Res. 2006 Nov 15;312(19):3909-19. doi: 10.1016/j.yexcr.2006.08.018. Epub 2006 Aug 30.


Intestinal epithelial cells interact with immune cells located in the intestinal epithelium via soluble factors. An in vitro model system using coculture was constructed to analyze the effect of macrophages on intestinal epithelial cells, and human intestinal epithelial-like Caco-2 monolayers and activated macrophage-like THP-1 cells were used in this study. Coculturing with THP-1 cells resulted in an increase of lactate dehydrogenase release from Caco-2 and a decrease in the transepithelial electrical resistance of the monolayers, showing that coculturing with THP-1 induced cell damage to Caco-2 cells. This disruption was significantly suppressed by adding anti-TNF-alpha antibody and etanercept, strongly suggesting that TNF-alpha secreted from THP-1 had caused cell damage to Caco-2 monolayers. The disrupted Caco-2 monolayers showed both apoptotic and necrotic characteristics by morphological and biochemical analyses. TNFRI and NF-kappaB seem to have been involved in this regulation. It is suggested that this phenomenon is similar in some respects to that observed with IBD and that this in vitro coculture system could be a good model for searching for the drugs or food substances that can be used to treat or prevent IBD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Apoptosis / physiology
  • Caco-2 Cells
  • Caspase 3 / metabolism
  • Caspase Inhibitors
  • Cell Line
  • Coculture Techniques
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Etanercept
  • Humans
  • Immunoglobulin G / pharmacology
  • Immunosuppressive Agents / pharmacology
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / prevention & control
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Intestines / immunology
  • Intestines / pathology*
  • L-Lactate Dehydrogenase / metabolism
  • Macrophage Activation
  • Necrosis
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Caspase Inhibitors
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • L-Lactate Dehydrogenase
  • Caspase 3
  • Etanercept