Hydroxylase Inhibition Abrogates TNF-α–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.

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

“…Tissue hypoxia and cytokines such as TNF-α are known triggers of cell death and turnover in the GIT (13,35). Histological evaluation revealed that chronic CS exposure resulted in increased numbers of mitotic cell profiles in colon crypts compared with normal air-exposed controls ( Figure 5A).…”

Hydroxylases as therapeutic targets in inflammatory bowel disease

“…60,61 While these initial studies utilized chemical models of acute colitis, subsequent studies using genetic-, ischemic-and toxin-based acute and chronic models support a protective role for hydroxylase inhibition in colitis. 44,45,62,63 More recently, the mechanisms underpinning the protective effects of hydroxylase inhibitors have become clearer (Figure 1). These mechanisms will be described below.…”

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

“…We observed reduced levels of TNF-a and IFN-γ under FTI and GGTI treatment. TNF-a was shown to cause epithelial damage 36 which could participate in damage to thymic epithelial cells and its reduction by FTI and GGTI would support thymic protection. IFN-γ was shown to cause thymic damage 37 and the reduced serum levels in animals treated with FTI and GGTI could contribute to thymic protection.…”