PMID- 14720504
OWN - NLM
STAT- MEDLINE
DCOM- 20040227
LR  - 20190707
IS  - 0014-4827 (Print)
IS  - 0014-4827 (Linking)
VI  - 292
IP  - 1
DP  - 2004 Jan 1
TI  - The effect of specific caspase inhibitors on TNF-alpha and butyrate-induced 
      apoptosis of intestinal epithelial cells.
PG  - 29-39
AB  - Tumour necrosis factor-alpha (TNF-alpha)-induced intestinal epithelial cell 
      apoptosis may contribute to mucosal injury in inflammatory bowel disease. 
      Inhibition of TNF-alpha-induced apoptosis, using specific caspase inhibitors 
      could, therefore, be of benefit in the treatment of disease. In vitro, CaCo-2 
      colonic epithelial cells are refractory to apoptosis induced by TNF-alpha alone; 
      however, TNF-alpha can act synergistically with the short-chain fatty acid (SCFA) 
      and colonic fermentation product, butyrate, to promote apoptosis. 
      TNF-alpha/butyrate-induced apoptosis was characterised by nuclear condensation 
      and fragmentation and caspase-3 activation. Inhibitors of caspase-8 (z-IETD.fmk) 
      and caspase-10 (z-AEVD.fmk) significantly reduced TNF-alpha/butyrate-induced 
      apoptosis, based on nuclear morphology and terminal deoxynucleotide 
      transferase-mediated dUTP-biotin nick-end labelling (TUNEL), although caspase 
      inhibition was associated with a significant increase in cells demonstrating 
      atypical nuclear condensation. Inclusion of atypical cells in calculations of 
      total cell death, still demonstrated that z-IETD.fmk and z-AEVD.fmk (in 
      combination) significantly reduced cell death. Reduction in cell death was 
      associated with maintenance of viable cell number. Transmembrane resistance was 
      also used a measure of the ability of caspase inhibitors to prevent 
      TNF-alpha/butyrate-mediated damage to epithelial monolayers. TNF-alpha/butyrate 
      resulted in a significant fall in transmembrane resistance, which was prevented 
      by pre-treatment with z-IETD.fmk, but not z-AEVD.fmk. In conclusion, synthetic 
      caspase inhibitors can reduce the apoptotic response of CaCo-2 colonic epithelial 
      cells to TNF-alpha/butyrate, improve the maintenance of viable cell numbers and 
      block loss of transmembrane resistance. We hypothesise that caspase inhibition 
      could be a useful therapeutic goal in the treatment of inflammatory bowel 
      conditions, such as ulcerative colitis.
FAU - Jones, Sarah A
AU  - Jones SA
AD  - Research Centre for Gastroenterology, Institute of Cell and Molecular Sciences, 
      Barts and The London, Queen Mary School of Medicine and Dentistry, University of 
      London, London EC1A 7BE, UK.
FAU - Butler, Ross N
AU  - Butler RN
FAU - Sanderson, Ian R
AU  - Sanderson IR
FAU - Wilson, James W
AU  - Wilson JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (Butyrates)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (Caspase 10)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.22.63 (CASP10 protein, human)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Butyrates/*pharmacology
MH  - Caco-2 Cells
MH  - Caspase 10
MH  - Caspase 3
MH  - Caspase 8
MH  - *Caspase Inhibitors
MH  - Caspases/metabolism
MH  - Cell Division/drug effects
MH  - Cell Nucleus/drug effects
MH  - Cell Survival/drug effects
MH  - Colorectal Neoplasms/*metabolism/pathology
MH  - Drug Synergism
MH  - Enzyme Activation
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2004/01/15 05:00
MHDA- 2004/02/28 05:00
CRDT- 2004/01/15 05:00
PHST- 2004/01/15 05:00 [pubmed]
PHST- 2004/02/28 05:00 [medline]
PHST- 2004/01/15 05:00 [entrez]
AID - S0014482703004440 [pii]
AID - 10.1016/j.yexcr.2003.08.005 [doi]
PST - ppublish
SO  - Exp Cell Res. 2004 Jan 1;292(1):29-39. doi: 10.1016/j.yexcr.2003.08.005.