Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling

Mario Cabrero Manresa, Murtaza M Tambuwala, Praveen Radhakrishnan, Jonathan M Harnoss, Eric Brown, Miguel A Cavadas, Ciara E Keogh, Alex Cheong, Kim E. Barrett, Eoin P Cummins, Martin Schneider, Cormac T Taylor

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Abstract

Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease (IBD), a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases (PHD), which confer oxygen-sensitivity upon the hypoxia inducible factor (HIF) pathway, has recently been shown to have therapeutic potential in colitis, although the mechanisms involved remain unclear. Here, we investigated the impact of hydroxylase inhibition on inflammation-driven fibrosis in a murine colitis model. Mice exposed to dextran sodium sulfate followed by period of recovery developed intestinal fibrosis characterized by alterations in the pattern of collagen deposition and infiltration of activated fibroblasts. Treatment with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) ameliorated fibrosis. TGF-β1 is a key regulator of fibrosis which acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-β1-induced expression of fibrotic markers in cultured fibroblasts suggesting a direct role for hydroxylases in TGF-β1 signalling. This was at least in part due to inhibition of non-canonical activation of extracellular signal-regulated kinase (ERK) signalling. In summary, pharmacologic hydroxylase inhibition ameliorates intestinal fibrosis, through suppression of TGF-β1-dependent ERK activation in fibroblasts. We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress pro-fibrotic pathways.
Original languageEnglish
Pages (from-to)G1076-G1090
Number of pages15
JournalAJP - Gastrointestinal and Liver Physiology
Volume311
Issue number6
Early online date1 Dec 2016
DOIs
Publication statusPublished - 13 Dec 2016

Keywords

  • hypoxia
  • inflammatory bowel disease
  • intestinal fibrosis
  • Hydroxylase inhibition
  • Transforming growth factor-b1 signaling

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    Cabrero Manresa, M., Tambuwala, M. M., Radhakrishnan, P., Harnoss, J. M., Brown, E., Cavadas, M. A., Keogh, C. E., Cheong, A., Barrett, K. E., Cummins, E. P., Schneider, M., & Taylor, C. T. (2016). Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling. AJP - Gastrointestinal and Liver Physiology, 311(6), G1076-G1090. https://doi.org/10.1152/ajpgi.00229.2016