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

Abstract

BackgroundInhibition 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.MethodsIn 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”).FindingsWe 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.InterpretationOur 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.FundThis 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.

Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells

“…enhancing Treg but limiting effector T cell responses 28,29 , but also suggest that targeting the PGE2 pathway may potentially be of beneficial in the control of intestinal inflammation. Our findings are further supported by a recent study demonstrating that PGE2 exacerbates TNF-induced inflammatory responses in human intestinal epithelial cells from patients with IBD who are resistant to TNF inhibitor therapy 46 . Moreover, recent studies including ourselves have suggested that lack of PGE2-EP4 signaling in T cells reduced both chemical-triggered acute and naïve T cell transfer-induced chronic intestinal inflammation, associated with reduction of inflammatory Th1 and/or Th17 cell responses 29,47,48 .…”

Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

“…Regardless of selective COX-2 inhibitors (COXIBS) manifested less GI damage [40], it is known that COX-2 has an essential role in enterocyte wound healing, through a mechanism related with NFKβ via and p38MAPK-dependent histone 3 phosphorylation, which is an important component of the intestinal wound-healing response [17], additionally PGE 2 participates in the differentiation of human goblet intestinal epithelial cells during homeostatic conditions [41] and PGI 2 in angiogenesis [10]. Bile salts seems also be related with intestinal damage cause by NSAIDs by forming super-toxic micelles [42,43], injuries that could be avoided by PC [44] evidencing the role of mucus barrier as protective factor of GI mucosa from lesions generated by NSAIDs.…”

Systematic Investigation of the Efficacy of Sinitang Decoction Against Ulcerative Colitis

“…TNF- α , PGE 2 , and IL-6 also play an important role in the inflammatory injury involved in UC ( Yamamoto et al, 2000 ; Gombošová et al, 2011 ; El Morsy et al, 2015 ; Sadar et al, 2016 ; El-Ashmawy et al, 2017 ; Gawrońska et al, 2017 ; Rafa et al, 2017 ; Li et al, 2018 ; Loynes et al, 2018 ). Moreover, GO analysis indicated that the proteins regulated by SNT in order to mediate its effects of UC play important roles in the pathogenesis of UC by regulating neutrophil degranulation, cell secretion, and other biological pathways.…”