Role of sphingosine kinase and sphingosine-1-phosphate in inflammatory arthritis

Lai, Wen‐Qi

doi:10.4331/wjbc.v1.i11.321

Cited by 19 publications

(7 citation statements)

References 72 publications

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“…It has been shown that sphingosine kinase (SphK) plays a role in inflammatory disorders, such as rheumatoid arthritis [21, 22]. However, the molecular details of S1P signaling in the regulation of inflammation remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells

Zhang

Jawadi

et al. 2013

Prostaglandins & Other Lipid Mediators

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Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions in endothelial cells. We previously showed that S1P receptor subtype 2 (S1P2) is significantly up-regulated in the atherosclerotic endothelium (J. Biol. Chem. 283:30363, 2008). In this study, we investigated the roles of S1P2-mediated signaling in the proinflammatory responses of endothelial cells. Treatment with tumor necrosis factor-α (TNFα), a proinflammatory cytokine, increased the expression of S1P2 receptors in endothelial cells. TNFα treatment also enhanced sphingosine kinase 1 expression and increased S1P production. Pharmacological inhibition or knockdown of S1P2 receptors completely abrogated the TNFα-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression in endothelial cells. In contrast, pharmacological inhibition or knockdown of other S1P receptor subtypes had no effect on the TNFα-stimulated ICAM-1 and VCAM-1 expression. Moreover, ectopic expression of S1P2 receptors increased VCAM-1 and ICAM-1 expression in endothelial cells in response to S1P stimulation. Mechanistically, we show that antagonizing S1P2 signaling markedly inhibited the TNFα-stimulated NFκB activation. Utilizing the NFκB reporter luciferase assay, the S1P/S1P2 signaling was shown to stimulate NFκB activation. Moreover, the S1P/S1P2-stimulated VCAM-1/ICAM-1 expression was completely abolished by the pharmacological inhibitor of NFκB. Collectively, our data suggest that TNFα treatment activates autocrine S1P/S1P2 signaling, which subsequently activates NFκB and leads to the proinflammatory responses in endothelial cells.

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Section: Introductionmentioning

confidence: 99%

Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells

Zhang

Jawadi

et al. 2013

Prostaglandins & Other Lipid Mediators

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“…Dysregulation of S1P concentrations are characteristic for an increasing number of diseases with disturbed immune modulation, especially autoimmune diseases (Bandhuvula and Saba, 2007 ; Brinkmann et al, 2010 ; Lai et al, 2011 ). Hence, it is of great importance to study the influence of S1P metabolism in association with survival and function of DCs.…”

Section: Discussionmentioning

confidence: 99%

Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1

et al. 2016

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Sphingosine 1-phosphate (S1P) is an immune modulatory lipid mediator and has been implicated in numerous pathophysiological processes. S1P is produced by sphingosine kinase 1 (Sphk1) and Sphk2. Dendritic cells (DCs) are central for the direction of immune responses and crucially involved in autoimmunity and cancerogenesis. In this study we examined the function and survival of bone marrow-derived DCs under long-term inflammatory stimulation. We observed that differentiated cells undergo activation-induced cell death (AICD) upon LPS stimulation with an increased metabolic activity shortly after stimulation, followed by a rapid activation of caspase 3 and subsequent augmented apoptosis. Importantly, we highlight a profound role of Sphk1 in secretion of inflammatory cytokines and survival of dendritic cells that might be mediated by a change in sphingolipid levels as well as by a change in STAT3 expression. Cell growth during differentiation of Sphk1-deficient cells treated with the functional S1P receptor antagonist FTYP was reduced. Importantly, in dendritic cells we did not observe a compensatory regulation of Sphk2 mRNA in Sphk1-deficient cells. Instead, we discovered a massive increase in Sphk1 mRNA concentration upon long-term stimulation with LPS in wild type cells that might function as an attempt to rescue from inflammation-caused cell death. Taken together, in this investigation we describe details of a crucial involvement of sphingolipids and Sphk1 in AICD during long-term immunogenic activity of DCs that might play an important role in autoimmunity and might explain the differences in immune response observed in in vivo studies of Sphk1 modulation.

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“…) is a key lipid kinase in sphingolipid metabolic pathway, which phosphorylate phingosine into sphingosine-1-phosphate (S1P) [20][21]. The importance of SPHK and S1P in in ammation and angiogenesis has been demonstrated in many hyperproliferative/in ammatory diseases such as RA [22]. The level of S1P exhibits signi cantly higher than those non-in ammatory osteoarthritis counterparts [23].…”

Section: Sphk (Including Sphk1 and Sphk2mentioning

confidence: 99%

New perspective: the multi-targets mechanism of hydroxychloroquine in the treatment of rheumatoid arthritis based on network pharmacology

Xie

et al. 2020

Preprint

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Background Network pharmacology is a new method of bioinformatics in exploring drug targets in recent 3 years. Hydroxychloroquine (HCQ) is a multi-targets drug that are clinically effective in rheumatoid arthritis (RA) but whose mechanism is not well understood. Methods The predicted targets of HCQ and the proteins related to RA were returned from databases. Followed by protein-protein interaction (PPI) network, the intersection of the two group of proteins was conducted. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was used to analyse these proteins in a macro perspective. Finally, the candidate targets were verified by molecular docking. Results The results suggest that the efficacy of HCQ against RA is mainly associated with 4 targets of smoothened homolog (SMO), sphingosine kinase (SPHK) 1, SPHK2 and gatty-acid amide hydrolase (FAAH), with their related 3316 proteins’ network which regulate ErbB, HIF-1, NF-κB, FoxO, Chemokine, MAPK, PI3K/Akt pathways and so forth. Biological process are mainly concentrated in the regulation of cell activation, myeloid leukocyte activation, regulated exocytosis and so forth. Molecular docking analysis shows that hydrogen bonding and π-π stacking are the main forms of chemical force. Conclusions Our research provides protein targets affected by HCQ in the treatment of RA. SMO, SPHK1, SPHK2 and FAAH involving 3316 proteins become the multi-targets mechanism of HCQ in the treatment of RA. As well, the research also provides a new idea for introducing network pharmacology into the evaluation of the multi-target drugs in internal medicine.

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Role of sphingosine kinase and sphingosine-1-phosphate in inflammatory arthritis

Cited by 19 publications

References 72 publications

Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells

Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells

Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1

New perspective: the multi-targets mechanism of hydroxychloroquine in the treatment of rheumatoid arthritis based on network pharmacology

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