Epithelial EP4 plays an essential role in maintaining homeostasis in colon

Matsumoto, Y; Nakanishi, Yuki; Yoshioka, Taiyo; Yamaga, Yuichi; Masuda, Tomonori; Fukunaga, Yosuke; Sono, Makoto; Yoshikawa, Takaaki; Nagao, Munemasa; Araki, Osamu; Ogawa, Satoshi; Goto, Norihiro; Hiramatsu, Yukiko; Breyer, Richard M.; Fukuda, Akira; Seno, Hiroshi

doi:10.1038/s41598-019-51639-2

Cited by 14 publications

(11 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tuft cells can direct production of prostaglandin E2, whereas SecPDG progenitors express the PGE2 receptor Ptger4 (Fig. 6d), an expression pattern that could explain why knockout of Ptger4 in the intestine leads to the loss of secretory cells 69 . Another class of prostaglandin receptor, peroxisome proliferator-activated receptors alpha and gamma (Ppara and Pparg) are most highly expressed in the absorptive lineage, implying that prostaglandins have different roles in the two lineages (Supplement 25d) [70][71][72] .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt

et al. 2020

View full text Add to dashboard Cite

Intestinal stem cells are non-quiescent, dividing epithelial cells that rapidly differentiate into progenitor cells of the absorptive and secretory cell lineages. The kinetics of this process is rapid such that the epithelium is replaced weekly. To determine how the transcriptome and proteome keep pace with rapid differentiation, we developed a new cell sorting method to purify mouse colon epithelial cells. Here we show that alternative mRNA splicing and polyadenylation dominate changes in the transcriptome as stem cells differentiate into progenitors. In contrast, as progenitors differentiate into mature cell types, changes in mRNA levels dominate the transcriptome. RNA processing targets regulators of cell cycle, RNA, cell adhesion, SUMOylation, and Wnt and Notch signaling. Additionally, global proteome profiling detected >2,800 proteins and revealed RNA:protein patterns of abundance and correlation. Paired together, these data highlight new potentials for autocrine and feedback regulation and provide new insights into cell state transitions in the crypt.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Thus, in cell culture models of colonic epithelia, prostaglandin-mediated signalling via the EP2 receptor prevented the proteosomal degradation of Claudin-4 [ 64 ]. The colon of EP4 deficient mice showed increased rates of apoptotic cells, as well as a defective mucosal barrier with signs of inflammation [ 65 ]. Furthermore, PGE2 was found to stimulate the recovery of the barrier function in porcine ischemia-injured ileal mucosa [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

The TRPA1 Agonist Cinnamaldehyde Induces the Secretion of HCO3− by the Porcine Colon

Manneck

Manz

Braun³

et al. 2021

IJMS

View full text Add to dashboard Cite

A therapeutic potential of the TRPA1 channel agonist cinnamaldehyde for use in inflammatory bowel disease is emerging, but the mechanisms are unclear. Semi-quantitative qPCR of various parts of the porcine gastrointestinal tract showed that mRNA for TRPA1 was highest in the colonic mucosa. In Ussing chambers, 1 mmol·l−1 cinnamaldehyde induced increases in short circuit current (ΔIsc) and conductance (ΔGt) across the colon that were higher than those across the jejunum or after 1 mmol·l−1 thymol. Lidocaine, amiloride or bumetanide did not change the response. The application of 1 mmol·l−1 quinidine or the bilateral replacement of 120 Na+, 120 Cl− or 25 HCO3− reduced ΔGt, while the removal of Ca2+ enhanced ΔGt with ΔIsc numerically higher. ΔIsc decreased after 0.5 NPPB, 0.01 indometacin and the bilateral replacement of 120 Na+ or 25 HCO3−. The removal of 120 Cl− had no effect. Cinnamaldehyde also activates TRPV3, but comparative measurements involving patch clamp experiments on overexpressing cells demonstrated that much higher concentrations are required. We suggest that cinnamaldehyde stimulates the secretion of HCO3− via apical CFTR and basolateral Na+-HCO3− cotransport, preventing acidosis and damage to the epithelium and the colonic microbiome. Signaling may involve the opening of TRPA1, depolarization of the epithelium and a rise in PGE2 following a lower uptake of prostaglandins via OATP2A1.

show abstract

“…It is well known to act through 4 kinds of receptor subtypes, EP 1 , EP 2 , EP 3 , and EP 4 , which mediate different signaling [ 12 ]. Among the EP receptor subtypes, EP 4 plays a pivotal role in regulating pathological events in IBD, as well as in maintaining gastrointestinal homeostasis [ 13 – 15 ]. An evaluation of biopsies from patients with IBD showed that both COX-2 expression and PGE 2 production increase during active phases of the disease [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate–induced colitis in mice lacking microsomal prostaglandin E synthase-1

et al. 2022

View full text Add to dashboard Cite

Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD.

show abstract

Epithelial EP4 plays an essential role in maintaining homeostasis in colon

Cited by 14 publications

References 25 publications

Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt

Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt

The TRPA1 Agonist Cinnamaldehyde Induces the Secretion of HCO3− by the Porcine Colon

Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate–induced colitis in mice lacking microsomal prostaglandin E synthase-1

Contact Info

Product

Resources

About