Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD.

Abstract

Hydroxylase inhibitors stabilize hypoxia-inducible factor-1 (HIF-1), which has barrier-protective activity in the gut. Because the inflammatory cytokine TNF-α contributes to inflammatory bowel disease in part by compromising intestinal epithelial barrier integrity, hydroxylase inhibition may have beneficial effects in TNF-α-induced intestinal epithelial damage. The hydroxylase inhibitor dimethyloxalylglycin (DMOG) was tested in a murine model of TNF-α-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-α-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-1α-dependent manner. Loss of this FADD repression by HIF-1α-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.

• Authors: Pieter Hindryckx, Martine De Vos, Peggy Jacques, Liesbeth Ferdinande, Harald Peeters, Kim Olievier, Sara Bogaert, Brigitta Brinkman, Peter Vandenabeele, Dirk Elewaut, Debby Laukens
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 10 Pg. 6306-16 (Nov 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20943999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids, Dicarboxylic
• Enzyme Inhibitors
• Fadd protein, mouse
• Fas-Associated Death Domain Protein
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Tumor Necrosis Factor-alpha
• Mixed Function Oxygenases
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic (pharmacology)
• Animals
• Blotting, Western
• Cell Hypoxia (genetics, immunology)
• Chromatin Immunoprecipitation
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Fas-Associated Death Domain Protein (genetics, metabolism)
• Gene Expression Regulation (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Ileitis (genetics, metabolism)
• Immunity, Mucosal (genetics, immunology)
• Immunohistochemistry
• Intestinal Mucosa (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mixed Function Oxygenases (antagonists & inhibitors)
• Promoter Regions, Genetic (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (metabolism)