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Epac-2 ameliorates spontaneous colitis in Il-10^-/- mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

ABSTRACT: Intestinal barrier dysfunction and intestinal inflammation interact in the progression of Crohn's disease (CD). A recent study indicated that Epac-2 protected the intestinal barrier and had anti-inflammatory effects. The present study examined the function of Epac-2 in CD-like colitis. Interleukin-10 gene knockout (Il-10^-/- ) mice exhibit significant spontaneous enteritis and were used as the CD model. These mice were treated with Epac-2 agonists (Me-cAMP) or Epac-2 antagonists (HJC-0350) or were fed normally (control), and colitis and intestinal barrier structure and function were compared. A Caco-2 and RAW 264.7 cell co-culture system were used to analyse the effects of Epac-2 on the cross-talk between intestinal epithelial cells and inflammatory cells. Epac-2 activation significantly ameliorated colitis in mice, which was indicated by reductions in the colitis inflammation score, the expression of inflammatory factors and intestinal permeability. Epac-2 activation also decreased Caco-2 cell permeability in an LPS-induced cell co-culture system. Epac-2 activation significantly suppressed nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signalling in vivo and in vitro. Epac-2 may be a therapeutic target for CD based on its anti-inflammatory functions and protective effects on the intestinal barrier.

SUBMITTER: Song X

PROVIDER: S-EPMC8742196 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Epac-2 ameliorates spontaneous colitis in Il-10<sup>-/-</sup> mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

Song Xue X Wen Hexin H Zuo Lugen L Zuo Lugen L Geng Zhijun Z Nian Jing J Wang Luyao L Jiang Yifan Y Tao Jing J Zhu Zihan Z Wu Xiaopei X Wang Zhikun Z Zhang Xiaofeng X Yu Liang L Zhao Hao H Xiang Ping P Li Jing J Shen Lin L Hu Jianguo J

Journal of cellular and molecular medicine 20211203 1

Intestinal barrier dysfunction and intestinal inflammation interact in the progression of Crohn's disease (CD). A recent study indicated that Epac-2 protected the intestinal barrier and had anti-inflammatory effects. The present study examined the function of Epac-2 in CD-like colitis. Interleukin-10 gene knockout (Il-10<sup>-/-</sup> ) mice exhibit significant spontaneous enteritis and were used as the CD model. These mice were treated with Epac-2 agonists (Me-cAMP) or Epac-2 antagonists (HJC-0 ...[more]

PMID: 34862717

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Project description:Background and purposeKalopanaxsaponin A, a triterpenoid saponin isolated from Kalopanax pictus (family Araliaceae), potently inhibited nuclear factor-kappa B (NF-κB) activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages during a screening programme for anti-colitis agents from natural products. Its anti-inflammatory mechanism remains unknown. Therefore, we investigated its anti-inflammatory effects in lipopolysaccharide (LPS)- or peptidoglycan-stimulated murine peritoneal macrophages and trinitrobenzene sulphonic acid (TNBS)-induced colitic mice.Experimental approachPeritoneal macrophages from male ICR mice were stimulated with LPS or peptidoglycan in vitro and treated with kalopanaxsaponin A. Colitis was induced in vivo by intrarectal administration of TNBS in male ICR mice. Mice were treated daily with kalopanaxsaponin A, sulphasalazine or phosphate-buffered saline. Inflammatory markers, cytokines, enzymes and transcription factors were measured by ELISA, immunoblot, flow cytometry and immunofluorescent confocal microscopy.Key resultsKalopanaxsaponin A potently inhibited the expression of the pro-inflammatory cytokines, interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6, induced by LPS, but not that induced by TNF-α, in peritoneal macrophages. However, it potently increased the expression of the anti-inflammatory cytokine IL-10. Kalopanaxsaponin A inhibited activation of the IL-1 receptor-associated kinase (IRAK)-1, inhibitor of κB kinase-β, NF-κB and mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun NH(2) -terminal kinase, p-38), but LPS/Toll-like receptor-4 interaction and IRAK-4 activation were not affected. Oral administration of kalopanaxsaponin A (10 and 20 mg·kg(-1) ) improved the clinical parameters and histology in vivo. Kalopanaxsaponin A inhibited NF-κB and mitogen-activated protein kinase activation induced by TNBS by suppressing IRAK-1 activation.Conclusions and implicationsKalopanaxsaponin A may improve inflammatory diseases, such as colitis, by inhibiting IRAK-1 activation.

Dataset Information

Epac-2 ameliorates spontaneous colitis in Il-10^-/- mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

Publications

Epac-2 ameliorates spontaneous colitis in Il-10<sup>-/-</sup> mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

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Dataset Information

Epac-2 ameliorates spontaneous colitis in Il-10-/- mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

Publications

Epac-2 ameliorates spontaneous colitis in Il-10<sup>-/-</sup> mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Epac-2 ameliorates spontaneous colitis in Il-10^-/- mice by protecting the intestinal barrier and suppressing NF-κB/MAPK signalling.