Hydroxylases regulate 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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.
LanguageEnglish
PagesG1076-G1090
JournalAJP - Gastrointestinal and Liver Physiology
Volume311
Issue number6
DOIs
Publication statusPublished - 1 Dec 2016

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Extracellular Signal-Regulated MAP Kinases
Mixed Function Oxygenases
Fibrosis
Fibroblasts
Colitis
Oxygen
Prolyl Hydroxylases
Dextran Sulfate
Inflammatory Bowel Diseases
Collagen
Inflammation
Therapeutics

Keywords

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

Cite this

Cabrero Manresa, M., Tambuwala, M. M., Radhakrishnan, P., Harnoss, J. M., Brown, E., Cavadas, M. A., ... Taylor, C. T. (2016). Hydroxylases regulate 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
Cabrero Manresa, Mario ; Tambuwala, Murtaza M ; Radhakrishnan, Praveen ; Harnoss, Jonathan M ; Brown, Eric ; Cavadas, Miguel A ; Keogh, Ciara E ; Cheong, Alex ; Barrett, Kim E. ; Cummins, Eoin P ; Schneider, Martin ; Taylor, Cormac T. / Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling. In: AJP - Gastrointestinal and Liver Physiology. 2016 ; Vol. 311, No. 6. pp. G1076-G1090.
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Cabrero Manresa, M, Tambuwala, MM, Radhakrishnan, P, Harnoss, JM, Brown, E, Cavadas, MA, Keogh, CE, Cheong, A, Barrett, KE, Cummins, EP, Schneider, M & Taylor, CT 2016, 'Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling', AJP - Gastrointestinal and Liver Physiology, vol. 311, no. 6, pp. G1076-G1090. https://doi.org/10.1152/ajpgi.00229.2016

Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling. / Cabrero Manresa, Mario; Tambuwala, Murtaza M; Radhakrishnan, Praveen; Harnoss, Jonathan M; Brown, Eric; Cavadas, Miguel A; Keogh, Ciara E; Cheong, Alex; Barrett, Kim E.; Cummins, Eoin P; Schneider, Martin; Taylor, Cormac T.

In: AJP - Gastrointestinal and Liver Physiology, Vol. 311, No. 6, 01.12.2016, p. G1076-G1090.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling

AU - Cabrero Manresa, Mario

AU - Tambuwala, Murtaza M

AU - Radhakrishnan, Praveen

AU - Harnoss, Jonathan M

AU - Brown, Eric

AU - Cavadas, Miguel A

AU - Keogh, Ciara E

AU - Cheong, Alex

AU - Barrett, Kim E.

AU - Cummins, Eoin P

AU - Schneider, Martin

AU - Taylor, Cormac T

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

KW - hypoxia

KW - inflammatory bowel disease

KW - intestinal fibrosis

KW - Hydroxylase inhibition

KW - Transforming growth factor-b1 signaling

U2 - 10.1152/ajpgi.00229.2016

DO - 10.1152/ajpgi.00229.2016

M3 - Article

VL - 311

SP - G1076-G1090

JO - AJP - Gastrointestinal and Liver Physiology

T2 - AJP - Gastrointestinal and Liver Physiology

JF - AJP - Gastrointestinal and Liver Physiology

SN - 0193-1857

IS - 6

ER -