Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.

Cohn, Steven M.; Schloemann, Suzanne; Tessner, Teresa G.; Seibert, Karen; Stenson, William F.

doi:10.1172/jci119296

Cited by 208 publications

(173 citation statements)

References 38 publications

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“…On one hand, as demonstrated by our data, high levels of PGE 2 analogs exacerbate clinical colitis, presumably through the induction of the IL-233 IL-17 proinflammatory axis. On the other hand, constitutive PGE 2 production in the intestine appears to have a protective effect on the integrity of the epithelial intestinal wall, presumably through the enhancement of epithelium survival and regeneration (45,64,65). This is evident primarily in models of colitis where the central event is damage to the epithelial layer, such as dextran sodium sulfate-induced colitis, and in experimental models using Cox1/2-or EP4-deficient mice, where PGE 2 synthesis or signaling of constitutive PGE 2 through the EP4 receptor are prevented (65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

252

196

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Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

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Section: Discussionmentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

252

196

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“…Cells incorporating BrdU were detected using a goat antiBrdU (9), and bound antibody was visualized using horseradish peroxidase-labeled donkey anti-goat IgG followed by staining with 3,3Ј-diaminobenzidine. A surviving crypt was defined as one containing five or more BrdU-positive cells as previously described (10). The number of surviving crypts per cross section was determined for each mouse by scoring the number of surviving crypts in at least eight complete, welloriented cross sections and dividing the total by the number of cross sections scored.…”

Section: Methodsmentioning

confidence: 99%

“…COX-1 is constitutively expressed in the mouse gastrointestinal tract; it can, however, be induced by radiation injury (10). COX-2 is barely detectable in the gastrointestinal tract under normal conditions, but it is induced in response to a wide variety of proinflammatory cytokines and mitogenic stimuli, including IL-1␤ and TNF-␣ (46,48,50), and is upregulated in some epithelial neoplasms (14,15,54).…”

mentioning

confidence: 99%

“…We have previously shown that COX-1 is markedly induced in the regenerative crypt epithelium 3.5 days after 13 Gy ␥-irradiation in adult mice and the PGE 2 produced is synthesized primarily through COX-1 and regulates intestinal stem cell survival after radiation (10). In contrast, PGE 2 synthesized in response to LPS stimulation is synthesized primarily through COX-2 (43) and mediates radioprotection.…”

mentioning

confidence: 99%

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Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Houchen

Sturmoski

Anant

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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The biological activities of PGE2 are mediated through EP receptors (EP1–EP4), plasma membrane G protein-coupled receptors that differ in ligand binding and signal-transduction pathways. We investigated gastrointestinal EP2 receptor expression in adult mice before and after radiation injury and evaluated intestinal stem cell survival and crypt epithelial apoptosis after radiation injury in EP2 null mice. EP2 was expressed throughout the gut. Intestinal EP2 mRNA increased fivefold after γ-irradiation. Crypt survival was diminished in EP2 −/− mice (4.06 crypts/cross section) compared with wild-type littermates (8.15 crypts/cross section). Radiation-induced apoptosis was significantly increased in EP2 −/− mice compared with wild-type littermates. Apoptosis was 1.6-fold higher in EP2 −/− mice (5.9 apoptotic cells/crypt) than in wild-type mice (3.5 apoptotic cells/crypt). The EP2receptor is expressed in mouse gastrointestinal epithelial cells and is upregulated following radiation injury. The effects of PGE2on both crypt epithelial apoptosis and intestinal crypt stem cell survival are mediated through the EP2 receptor.

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“…This dose of indomethacin was reported to inhibit PGE2 production in mice in vivo. 13,24 The degree of inflammation was histologically scored as previously described. 25 Briefly, scores of inflammation were 0, no increased inflammatory infiltrates; 1, focal mild inflammation; 2, diffuse mild inflammation; 3, cryptic abscess formation; and 4, diffuse dense inflammation.…”

Section: Induction Of Colitismentioning

confidence: 99%

Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate‐induced colitis in mice

et al. 2010

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The aryl hydrocarbon receptor (AhR) recognizes numerous small xenobiotic and natural molecules, such as dioxin and natural chemicals, and is involved in the metabolism of these compounds. AhR also has a regulatory role in inflammatory responses. This study investigated whether the activation of the AhR pathway affects dextran sodium sulfate (DSS)-induced colitis, an ulcerative colitis-like model, in mice. DSS-induced colitis was ameliorated by pretreatment with a potent AhR activator, 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), in mice. In addition, the mice pretreated with TCDD showed increased prostaglandin E2 (PGE2) production in the colon, and inhibition of PGE2 production by indomethacin abrogated the inhibitory effects of TCDD on DSS-induced colitis. Collectively, the activation of the AhR pathway by TCDD may ameliorate DSS-induced colitis, at least in part, through PGE2 production.

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Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.

Cited by 208 publications

References 38 publications

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate‐induced colitis in mice

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Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.

Cited by 208 publications

References 38 publications

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Prosurvival and antiapoptotic effects of PGE2in radiation injury are mediated by EP2receptor in intestine

Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate‐induced colitis in mice

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Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine