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      Clonorchis sinensis lysophospholipase A upregulates IL-25 expression in macrophages as a potential pathway to liver fibrosis

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          Abstract

          Background

          Liver fibrosis is an excessive wound-healing reaction that requires the participation of inflammatory cells and hepatic stellate cells (HSCs). The pathogenesis of liver fibrosis caused by viruses and alcohol has been well characterized, but the molecular mechanisms underlying liver fibrosis induced by the liver fluke Clonorchis sinensis are poorly understood. Lysophospholipase A (LysoPLA), which deacylates lysophospholipids, plays a critical role in mediating the virulence and pathogenesis of parasites and fungi; however, the roles of C. sinensis lysophospholipase A ( CsLysoPLA) in C. sinensis-induced liver fibrosis remain unknown.

          Methods

          A mouse macrophage cell line (RAW264.7) was cultured and treated with CsLysoPLA. IL-25 and members of its associated signaling pathway were detected by performing quantitative real-time PCR, Western blotting and immunofluorescent staining. A human hepatic stellate cell line (LX-2) was cultured and exposed to IL-25. LX-2 cell activation markers were examined via quantitative real-time PCR, Western blotting and immunofluorescent staining. Migration was analyzed in transwell plates.

          Results

          Treating RAW264.7 cells with CsLysoPLA significantly induced IL-25 expression. Elevated PKA, B-Raf, and ERK1/2 mRNA levels and phosphorylated B-Raf and ERK1/2 were detected in CsLysoPLA-stimulated RAW264.7 cells. The PKA inhibitor H-89 weakened B-Raf and ERK1/2 phosphorylation whereas the AKT activator SC79 attenuated ERK1/2 phosphorylation in RAW264.7 cells. Both H-89 and SC79 inhibited CsLysoPLA-induced IL-25 upregulation. In addition, stimulation of LX-2 cells with IL-25 upregulated the expression of mesenchymal cell markers, including α-smooth muscle actin (α-SMA) and collagen type I (Collagen-I), and promoted cell migration.

          Conclusions

          CsLysoPLA activates HSCs by upregulating IL-25 in macrophages through the PKA-dependent B-Raf/ERK1/2 pathway and potentially promotes hepatic fibrosis during C. sinensis infection.

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          Most cited references34

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          Causal protein-signaling networks derived from multiparameter single-cell data.

          Machine learning was applied for the automated derivation of causal influences in cellular signaling networks. This derivation relied on the simultaneous measurement of multiple phosphorylated protein and phospholipid components in thousands of individual primary human immune system cells. Perturbing these cells with molecular interventions drove the ordering of connections between pathway components, wherein Bayesian network computational methods automatically elucidated most of the traditionally reported signaling relationships and predicted novel interpathway network causalities, which we verified experimentally. Reconstruction of network models from physiologically relevant primary single cells might be applied to understanding native-state tissue signaling biology, complex drug actions, and dysfunctional signaling in diseased cells.
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            IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.

            We have characterized a cytokine produced by Th2 cells, designated as IL-25. Infusion of mice with IL-25 induced IL-4, IL-5, and IL-13 gene expression. The induction of these cytokines resulted in Th2-like responses marked by increased serum IgE, IgG(1), and IgA levels, blood eosinophilia, and pathological changes in the lungs and digestive tract that included eosinophilic infiltrates, increased mucus production, and epithelial cell hyperplasia/hypertrophy. In addition, our studies show that IL-25 induces Th2-type cytokine production by accessory cells that are MHC class II(high), CD11c(dull), and lineage(-). These results suggest that IL-25, derived from Th2 T cells, is capable of amplifying allergic type inflammatory responses by its actions on other cell types.
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              Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.

              W Kolch (2000)
              The Ras/Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, and how they contribute to co-ordinate activation steps, subcellular redistribution, substrate phosphorylation and cross-talk with other signalling pathways.
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                Author and article information

                Contributors
                291666138@qq.com
                774306317@qq.com
                244229456@qq.com
                542878159@qq.com
                tzl120016@126.com
                1228301050@qq.com
                710387301@qq.com
                lvzhiyue@mail.sysu.edu.cn
                xujin@mail.sysu.edu.cn
                huang66@mail.sysu.edu.cn
                yuhxteam@163.com
                Journal
                Parasit Vectors
                Parasit Vectors
                Parasites & Vectors
                BioMed Central (London )
                1756-3305
                17 June 2017
                17 June 2017
                2017
                : 10
                : 295
                Affiliations
                [1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Parasitology, Zhongshan School of Medicine, , Sun Yat-sen University, ; Guangzhou, China
                [2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Key Laboratory for Tropical Diseases Control, , Sun Yat-sen University, Ministry of Education, ; Guangzhou, Guangdong China
                Article
                2228
                10.1186/s13071-017-2228-z
                5474055
                28623940
                77101a5f-f973-402e-a715-a5dd081c87c2
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 January 2017
                : 2 June 2017
                Funding
                Funded by: the National Key Basic Research and Development Project
                Award ID: No. 2010CB530000
                Award Recipient :
                Funded by: the National Natural Science Foundation of China
                Award ID: No. 81101270
                Award Recipient :
                Funded by: the National Important Sci-Tech Special Projects
                Award ID: No. 2012ZX10004220
                Award Recipient :
                Funded by: the Science and Technology Planning Project of Guangdong Province
                Award ID: 2016A050502008
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Parasitology
                cslysopla,liver fibrosis,il-25
                Parasitology
                cslysopla, liver fibrosis, il-25

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