Dataset Information

COX-1/PGE₂/EP4 alleviates mucosal injury by upregulating ?-arr1-mediated Akt signaling in colitis.

ABSTRACT: COX-1/PGE₂ is an important protective mediator in ulcerative colitis (UC). ?-arrestin1 (?-arr1), which acts as a scaffold protein, is involved in PGE₂-mediated signaling pathways. However, the interaction between PGE₂ and ?-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE₂ were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE₂ treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, ?-arr1 deficient mice showed increased signs of colitis compared to ?-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in ?-arr1 deficient mice. In parallel, HCT116 cells transfected with ?-arr1 siRNA were examined in the presence or absence of PGE₂ in vitro. PGE₂ treatment in the ?-arr1 WT/KO DSS model and ?-arr1 siRNA transfection of HCT116 cells confirmed that PGE₂ upregulated ?-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE₂/EP4 upregulates the ?-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE₂ in UC.

SUBMITTER: Peng X

PROVIDER: S-EPMC5430694 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis.

Peng Xiaojie X Li Jianzhong J Tan Siwei S Xu Minyi M Tao Jin J Jiang Jie J Liu Huiling H Wu Bin B

Scientific reports 20170421 1

COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. ...[more]

PMID: 28432343

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Project description:BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism.MethodsSynovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1-4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry.ResultsTREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1-4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling.ConclusionsOur data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.

Project description:Acute liver injury (ALI) is a global health problem associated with high mortality and has attracted clinical attention. Ginkgo biloba extract (GBE) is an extract from dried Ginkgo leaves that has many pharmacological effects because of its various ingredients and has been shown to be hepatoprotective. We investigated the hepatoprotective effect of GBE on carbon tetrachloride (CCl4)-induced acute liver injury in vitro. The components of Ginkgo biloba extract are analyzed by LC-MS, and the key targets of "liver injury-Ginkgo biloba" are identified based on bioinformatics analysis. The signaling pathways such as PI3K/AKT are mainly enriched with high correlation in KEGG. The results of in vitro experiments showed that compared with the Model group, except that the ALT activity level and MDA content in EGB-L group were not significantly decreased (P > 0.05), the activity of ALT, AST and MDA content in other EGB groups were significantly decreased (P < 0.05), and the activities of SOD and CAT were significantly increased (P < 0.05). The expression of inflammatory factors IL-1β, IL-6 and TNF-α were also detected. The results showed that compared with the Model group, the contents of IL-6 in EGB-L group were not significantly decreased (P > 0.05), while the contents of IL-1β, IL-6 and TNF-α in other EGB groups were significantly decreased (P < 0.05), indicating that EGB could reduce the level of cell inflammation. Western blot assay detected the protein expression levels of GF, RTK, PI3K, AKT and p-AKT in cells. The results showed that compared with the Model group, the protein expression levels of GF, RTK, PI3K, AKT and P-AKT were significantly increased after EGB treatment (P < 0.05), and the protein expression level of the EGB-H group was higher than the EGB-L group. Ginkgo biloba extract can inhibit the expression of downstream related genes by activating PI3K/AKT signaling pathway, and at the same time alleviate the inflammatory response of cells, reduce the level of inflammation, and protect the cell damage caused by CCl4.

Dataset Information

COX-1/PGE₂/EP4 alleviates mucosal injury by upregulating ?-arr1-mediated Akt signaling in colitis.

Publications

COX-1/PGE<sub>2</sub>/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis.

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Dataset Information

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating ?-arr1-mediated Akt signaling in colitis.

Publications

COX-1/PGE<sub>2</sub>/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

COX-1/PGE₂/EP4 alleviates mucosal injury by upregulating ?-arr1-mediated Akt signaling in colitis.