PMID- 20943999
OWN - NLM
STAT- MEDLINE
DCOM- 20101202
LR  - 20161125
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 185
IP  - 10
DP  - 2010 Nov 15
TI  - Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage 
      by hypoxia-inducible factor-1-dependent repression of FADD.
PG  - 6306-16
LID - 10.4049/jimmunol.1002541 [doi]
AB  - Hydroxylase inhibitors stabilize hypoxia-inducible factor-1 (HIF-1), which has 
      barrier-protective activity in the gut. Because the inflammatory cytokine TNF-alpha 
      contributes to inflammatory bowel disease in part by compromising intestinal 
      epithelial barrier integrity, hydroxylase inhibition may have beneficial effects 
      in TNF-alpha-induced intestinal epithelial damage. The hydroxylase inhibitor 
      dimethyloxalylglycin (DMOG) was tested in a murine model of TNF-alpha-driven chronic 
      terminal ileitis. DMOG-treated mice experienced clinical benefit and showed clear 
      attenuation of chronic intestinal inflammation compared with that of 
      vehicle-treated littermates. Additional in vivo and in vitro experiments revealed 
      that DMOG rapidly restored terminal ileal barrier function, at least in part 
      through prevention of TNF-alpha-induced intestinal epithelial cell apoptosis. 
      Subsequent transcriptional studies indicated that DMOG repressed Fas-associated 
      death domain protein (FADD), a critical adaptor molecule in TNFR-1-mediated 
      apoptosis, in an HIF-1alpha-dependent manner. Loss of this FADD repression by 
      HIF-1alpha-targeting small interfering RNA significantly diminished the antiapoptotic 
      action of DMOG. Additional molecular studies led to the discovery of a previously 
      unappreciated HIF-1 binding site in the FADD promoter, which controls repression 
      of FADD during hypoxia. As such, the results reported in this study allowed the 
      identification of an innate mechanism that protects intestinal epithelial cells 
      during (inflammatory) hypoxia, by direct modulation of death receptor signaling. 
      Hydroxylase inhibition could represent a promising alternative treatment strategy 
      for hypoxic inflammatory diseases, including inflammatory bowel disease.
FAU - Hindryckx, Pieter
AU  - Hindryckx P
AD  - Department of Gastroenterology, Ghent University, Ghent, Belgium.
FAU - De Vos, Martine
AU  - De Vos M
FAU - Jacques, Peggy
AU  - Jacques P
FAU - Ferdinande, Liesbeth
AU  - Ferdinande L
FAU - Peeters, Harald
AU  - Peeters H
FAU - Olievier, Kim
AU  - Olievier K
FAU - Bogaert, Sara
AU  - Bogaert S
FAU - Brinkman, Brigitta
AU  - Brinkman B
FAU - Vandenabeele, Peter
AU  - Vandenabeele P
FAU - Elewaut, Dirk
AU  - Elewaut D
FAU - Laukens, Debby
AU  - Laukens D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101013
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Amino Acids, Dicarboxylic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fadd protein, mouse)
RN  - 0 (Fas-Associated Death Domain Protein)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - VVW38EB8YS (oxalylglycine)
SB  - IM
MH  - Amino Acids, Dicarboxylic/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Cell Hypoxia/genetics/immunology
MH  - Chromatin Immunoprecipitation
MH  - Enzyme Inhibitors/*pharmacology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fas-Associated Death Domain Protein/genetics/*metabolism
MH  - Gene Expression Regulation/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Ileitis/genetics/metabolism
MH  - Immunity, Mucosal/genetics/immunology
MH  - Immunohistochemistry
MH  - Intestinal Mucosa/*metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Mixed Function Oxygenases/*antagonists & inhibitors
MH  - Promoter Regions, Genetic/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2010/10/15 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/10/15 06:00
PHST- 2010/10/15 06:00 [entrez]
PHST- 2010/10/15 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - jimmunol.1002541 [pii]
AID - 10.4049/jimmunol.1002541 [doi]
PST - ppublish
SO  - J Immunol. 2010 Nov 15;185(10):6306-16. doi: 10.4049/jimmunol.1002541. Epub 2010 
      Oct 13.