Hypoxia-inducible factor (HIF) hydroxylase inhibition enhances the protective effects of cyclosporine in colitis.

Doug Halligan, Mohammed Khan, Eric Brown, Catherine Rowan, Ivan S Coulter, Glen Doherty, Murtaza M Tambuwala, Cormac T Taylor

Research output: Contribution to journalArticle

Abstract

Inflammatory Bowel Disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function an inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesised that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium (DSS) model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG administered alone ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to ZO-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.
LanguageEnglish
JournalAJP - Gastrointestinal and Liver Physiology
Publication statusAccepted/In press - 29 Apr 2019

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Colitis
Mixed Function Oxygenases
Cyclosporine
Anti-Inflammatory Agents
Inflammation
Inflammatory Bowel Diseases
Pharmaceutical Preparations
Dextran Sulfate
Immunosuppressive Agents
Inbred C57BL Mouse
Disease Progression
Hypoxia
Immune System
Up-Regulation
Epithelial Cells
oxalylglycine
Apoptosis
Antigens
Genes

Keywords

  • Inflammation
  • colitis
  • hydoxylase
  • cyclosporine

Cite this

Halligan, D., Khan, M., Brown, E., Rowan, C., Coulter, I. S., Doherty, G., ... Taylor, C. T. (Accepted/In press). Hypoxia-inducible factor (HIF) hydroxylase inhibition enhances the protective effects of cyclosporine in colitis. AJP - Gastrointestinal and Liver Physiology.
Halligan, Doug ; Khan, Mohammed ; Brown, Eric ; Rowan, Catherine ; Coulter, Ivan S ; Doherty, Glen ; Tambuwala, Murtaza M ; Taylor, Cormac T. / Hypoxia-inducible factor (HIF) hydroxylase inhibition enhances the protective effects of cyclosporine in colitis. In: AJP - Gastrointestinal and Liver Physiology. 2019.
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Hypoxia-inducible factor (HIF) hydroxylase inhibition enhances the protective effects of cyclosporine in colitis. / Halligan, Doug; Khan, Mohammed; Brown, Eric ; Rowan, Catherine; Coulter, Ivan S; Doherty, Glen; Tambuwala, Murtaza M; Taylor, Cormac T.

In: AJP - Gastrointestinal and Liver Physiology, 29.04.2019.

Research output: Contribution to journalArticle

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AU - Halligan, Doug

AU - Khan, Mohammed

AU - Brown, Eric

AU - Rowan, Catherine

AU - Coulter, Ivan S

AU - Doherty, Glen

AU - Tambuwala, Murtaza M

AU - Taylor, Cormac T

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N2 - Inflammatory Bowel Disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function an inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesised that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium (DSS) model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG administered alone ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to ZO-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.

AB - Inflammatory Bowel Disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function an inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesised that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium (DSS) model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG administered alone ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to ZO-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.

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