COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis
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COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis. / Li, Yuan; Soendergaard, Christoffer; Bergenheim, Fredrik Holmberg; Aronoff, David M; Milne, Ginger; Riis, Lene Buhl; Seidelin, Jakob Benedict; Jensen, Kim B.; Nielsen, Ole Haagen.
I: EBioMedicine, Bind 36, 2018, s. 497-507.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 - Bergenheim, Fredrik Holmberg
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. Published by Elsevier B.V.
PY - 2018
Y1 - 2018
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.
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: 202228015