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      S1P promotes IL-6 expression in osteoblasts through the PI3K, MEK/ERK and NF-κB signaling pathways

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          Abstract

          Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks joint tissue. Interleukin (IL)-6 is a key proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we examined the effects of S1P on IL-6 expression in osteoblasts. Our results and records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-6 in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P increased mRNA and protein expression of IL-6. PI3K, MEK, ERK and NF-κB inhibitors and their small interfering RNAs (siRNAs) reduced S1P-promoted IL-6 expression. S1P also facilitated PI3K, MEK/ERK and NF-κB signaling cascades. Our results indicate that S1P promotes the expression of IL-6 in osteoblasts via the PI3K, MEK/ERK and NF-κB signaling pathways.

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          Cytokine pathways and joint inflammation in rheumatoid arthritis.

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            Cartilage damage in osteoarthritis and rheumatoid arthritis--two unequal siblings.

            Cartilage damage is a key feature of degenerative joint disorders-primarily osteoarthritis (OA)-and chronic inflammatory joint diseases, such as rheumatoid arthritis (RA). Substantial progress has been made towards understanding the mechanisms that lead to degradation of the cartilage matrix in either condition, which ultimately results in the progressive remodelling of affected joints. The available data have shown that the molecular steps in cartilage matrix breakdown overlap in OA and RA. However, they have also, to a great extent, changed our view of the roles of cartilage in the pathogenesis of these disorders. In OA, cartilage loss occurs as part of a complex programme that resembles aspects of embryonic bone formation through endochondral ossification. In RA, early cartilage damage is a key trigger of cellular reactions in the synovium. In a proposed model of RA as a site-specific manifestation of a systemic autoimmune disorder, early cartilage damage in the context of immune activation leads to a specific cellular response within articular joints that could explain not only the organ specificity of RA, but also the chronic nature and perpetuation of the disease.
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              Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells

              Background IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive. Methods In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs). Results We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways. Conclusions Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling. Electronic supplementary material The online version of this article (10.1186/s12964-018-0268-4) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2020
                18 May 2020
                : 17
                : 9
                : 1207-1214
                Affiliations
                [1 ]School of Medicine, China Medical University, Taichung, Taiwan
                [2 ]Department of Family Medicine, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
                [3 ]Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
                [4 ]Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
                [5 ]Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan
                [6 ]Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
                [7 ]Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
                [8 ]Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
                [9 ]Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
                [10 ]Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
                Author notes
                ✉ Corresponding authors: Chih-Hsin, Tang PhD, Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; E-mail: chtang@ 123456mail.cmu.edu.tw . Yi-Chin, Fong MD, PhD, Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan; E-mail: yichin.fong@ 123456gmail.com

                # These authors contributed equally.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv17p1207
                10.7150/ijms.44612
                7294913
                32547316
                0a32292b-23f7-49c1-8bf8-05cd0ec43f97
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 6 February 2020
                : 27 April 2020
                Categories
                Research Paper

                Medicine
                s1p,il-6,osteoblasts,arthritis
                Medicine
                s1p, il-6, osteoblasts, arthritis

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