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COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis

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@article{d1ecdcb5dc374355b291cde883c3a341,
title = "COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis",
abstract = "BACKGROUND: Inhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors.METHODS: In this study, COX-2 expression was analyzed in human intestinal biopsies and patient-derived monocytes, and the downstream consequences of COX-2 activity was evaluated by assessing the influence of the down-stream effector, PGE2, on intestinal epithelial stem cell self-renewal and differentiation using primary human intestinal organoids ({"}mini-guts{"}).FINDINGS: We found that TNF stimulation induced COX-2 expression in monocytes isolated from responders (Rs), whereas COX-2 expression was constitutively high and non-inducible in monocytes from PNRs. Additionally, PGE2 in combination with proliferative signals transformed human intestinal epithelial cells to a proinflammatory state akin to flaring UC, whereas PGE2 in combination with differentiation signals supported robust mucin induction.INTERPRETATION: Our work indicates that COX-2-PGE2 signaling could be a novel target for the management of PNRs to TNF inhibitors. We additionally demonstrate that COX-2-PGE2 signaling has dual functions during tissue repair and normal lineage differentiation, explaining in part the lack of response to TNF inhibitors among PNRs. FUND: This work was funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation, the Vanderbilt Digestive Disease Research Center, NIH Grants, Aase and Ejnar Danielsen's Foundation and the A.P. M{\o}ller Foundation.",
keywords = "Biomarkers, Biopsy, Cell Self Renewal/genetics, Colitis, Ulcerative/diagnosis, Cyclooxygenase 2/genetics, Dinoprostone/metabolism, Epithelial Cells/metabolism, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Intestinal Mucosa/metabolism, Monocytes/immunology, Regeneration, Signal Transduction/drug effects, Stem Cells/cytology, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Wound Healing",
author = "Yuan Li and Christoffer Soendergaard and Frederik Holmberg and Aronoff, {David M} and Ginger Milne and Riis, {Lene Buhl} and Seidelin, {Jakob Benedict} and Jensen, {Kim B} and Nielsen, {Ole Haagen}",
note = "Copyright {\textcopyright} 2018 The Authors. Published by Elsevier B.V. All rights reserved.",
year = "2018",
month = oct,
doi = "10.1016/j.ebiom.2018.08.040",
language = "English",
volume = "36",
pages = "497--507",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis

AU - Li, Yuan

AU - Soendergaard, Christoffer

AU - Holmberg, Frederik

AU - Aronoff, David M

AU - Milne, Ginger

AU - Riis, Lene Buhl

AU - Seidelin, Jakob Benedict

AU - Jensen, Kim B

AU - Nielsen, Ole Haagen

N1 - Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

PY - 2018/10

Y1 - 2018/10

N2 - BACKGROUND: Inhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors.METHODS: In this study, COX-2 expression was analyzed in human intestinal biopsies and patient-derived monocytes, and the downstream consequences of COX-2 activity was evaluated by assessing the influence of the down-stream effector, PGE2, on intestinal epithelial stem cell self-renewal and differentiation using primary human intestinal organoids ("mini-guts").FINDINGS: We found that TNF stimulation induced COX-2 expression in monocytes isolated from responders (Rs), whereas COX-2 expression was constitutively high and non-inducible in monocytes from PNRs. Additionally, PGE2 in combination with proliferative signals transformed human intestinal epithelial cells to a proinflammatory state akin to flaring UC, whereas PGE2 in combination with differentiation signals supported robust mucin induction.INTERPRETATION: Our work indicates that COX-2-PGE2 signaling could be a novel target for the management of PNRs to TNF inhibitors. We additionally demonstrate that COX-2-PGE2 signaling has dual functions during tissue repair and normal lineage differentiation, explaining in part the lack of response to TNF inhibitors among PNRs. FUND: This work was funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation, the Vanderbilt Digestive Disease Research Center, NIH Grants, Aase and Ejnar Danielsen's Foundation and the A.P. Møller Foundation.

AB - BACKGROUND: Inhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors.METHODS: In this study, COX-2 expression was analyzed in human intestinal biopsies and patient-derived monocytes, and the downstream consequences of COX-2 activity was evaluated by assessing the influence of the down-stream effector, PGE2, on intestinal epithelial stem cell self-renewal and differentiation using primary human intestinal organoids ("mini-guts").FINDINGS: We found that TNF stimulation induced COX-2 expression in monocytes isolated from responders (Rs), whereas COX-2 expression was constitutively high and non-inducible in monocytes from PNRs. Additionally, PGE2 in combination with proliferative signals transformed human intestinal epithelial cells to a proinflammatory state akin to flaring UC, whereas PGE2 in combination with differentiation signals supported robust mucin induction.INTERPRETATION: Our work indicates that COX-2-PGE2 signaling could be a novel target for the management of PNRs to TNF inhibitors. We additionally demonstrate that COX-2-PGE2 signaling has dual functions during tissue repair and normal lineage differentiation, explaining in part the lack of response to TNF inhibitors among PNRs. FUND: This work was funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation, the Vanderbilt Digestive Disease Research Center, NIH Grants, Aase and Ejnar Danielsen's Foundation and the A.P. Møller Foundation.

KW - Biomarkers

KW - Biopsy

KW - Cell Self Renewal/genetics

KW - Colitis, Ulcerative/diagnosis

KW - Cyclooxygenase 2/genetics

KW - Dinoprostone/metabolism

KW - Epithelial Cells/metabolism

KW - Gene Expression

KW - Gene Expression Profiling

KW - Humans

KW - Immunohistochemistry

KW - Intestinal Mucosa/metabolism

KW - Monocytes/immunology

KW - Regeneration

KW - Signal Transduction/drug effects

KW - Stem Cells/cytology

KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors

KW - Wound Healing

U2 - 10.1016/j.ebiom.2018.08.040

DO - 10.1016/j.ebiom.2018.08.040

M3 - Journal article

C2 - 30190207

VL - 36

SP - 497

EP - 507

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -

ID: 56370249