FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice

Ando, Seiichiro; Amano, Hirofumi; Amano, Eri; Minowa, Kentaro; Watanabe, Takashi; Nakano, Soichiro; Nakiri, Yutaka; Morimoto, Shinji; Tokano, Yoshiaki; Lin, Qingshun; Hou, Rong; Ohtsuji, Mareki; Tsurui, Hiromichi; Hirose, Sachiko; Takasaki, Yoshinari

doi:10.1016/j.bbrc.2010.03.078

Cited by 41 publications

(29 citation statements)

References 24 publications

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“…This study compared FTY720 to cyclophosphamide and suggested that FTY720 may be an acceptable alternative therapeutic in lupus nephritis. Interestingly, in the BXSB model FTY720 did not decrease the production of auto-antibodies, and IgG and C3 were detected in the glomeruli in FTY720-treated mice [64]. In this study, mice treated with FTY720 exhibited decreased proteinuria and increased survival with similar results as were demonstrated in the study using MRL/lpr mice.…”

Section: Lupussupporting

confidence: 80%

Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease

Snider¹

2013

International Journal of Clinical Rheumatology

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Sphingolipids and their metabolizing enzymes are beginning to be recognized as critical mediators in biological processes, specifically in inflammation and autoimmunity. Sphingosine kinases (SKs) and their lipid product sphingosine-1-phosphate (S1P) play essential roles in inflammatory signaling processes, as well as disease development and progression. SKs can be activated by numerous growth factors and cytokines, including TNF-α and IL-1β, leading to the generation of S1P. S1P exerts its biological effects on intracellular and extracellular targets, such as S1P receptors. In addition to roles in inflammatory signaling pathways SKs, S1P and S1P receptors have been implicated in immune cell function and trafficking, specifically in lymphocytes. This review will discuss the contribution of the bioactive sphingolipid S1P, its generating enzyme SK, and its cell surface receptors in the inflammatory and autoimmune diseases systemic lupus erythematosus, arthritis and inflammatory bowel disease.

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Section: Lupussupporting

confidence: 80%

Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease

Snider¹

2013

International Journal of Clinical Rheumatology

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“…(Of note here, there were no significant differences in survival between vehicle and ABC294640 groups, as the study was conducted only until 20 weeks to examine pathobiological changes with ABC294640 as opposed to effect on survival – data not shown). FTY720 treatment also exhibited decreased mesangial cell proliferation and inflammatory cell infiltration into the kidney [6]. Of note, for FTY720 to be activated and act on S1PRs, it must first be phosphorylated by SK2, suggesting that SK2 is active in lupus.…”

Section: Discussionmentioning

confidence: 98%

“…The majority of S1P actions are thought to involve S1P receptors 1–5 (S1PR 1–5), G protein-coupled receptors that are differentially expressed. These receptors can act through several different signaling pathways: S1PR1 and S1PR3 ultimately activate Rac to alter stress fiber function and promote cell migration toward S1P, and have been implicated in LN [5], [6]. S1PR1 has been demonstrated to play an essential role in the egress of lymphocytes from the lymph nodes into inflamed tissue and highlights the importance of S1P in immunity [7].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Sphingosine Kinase-2 in a Murine Model of Lupus Nephritis

et al. 2013

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Sphingosine-1-phosphate (S1P), a potent bioactive lipid, is emerging as a central mediator in inflammation and immune responses. We have previously implicated S1P and its synthetic enzyme sphingosine kinase (SK) in inflammatory and autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis. Generation of S1P requires phosphorylation of sphingosine by SK, of which there are two isoforms. Numerous studies have implicated SK1 in immune cell trafficking, inflammation and autoimmune disorders. In this study, we set out to determine the role of SK and S1P in lupus nephritis (LN). To this end, we examined S1P and dihydro-S1P (dh-S1P) levels in serum and kidney tissues from a mouse model of LN. Interestingly dh-S1P was significantly elevated in serum and kidney tissue from LN mice, which is more readily phosphorylated by SK2. Therefore, we employed the use of the specific SK2 inhibitor, ABC294640 in our murine model of LN. Treatment with ABC294640 did not improve vascular or interstitial pathology associated with LN. However, mice treated with the SK2 inhibitor did demonstrate decreases in glomerular pathology and accumulation of B and T cells in the spleen these were not statistically different from lpr mice treated with vehicle. LN mice treated with ABC294640 did not have improved urine thromboxane levels or urine proteinuria measurements. Both S1P and dh-S1P levels in circulation were significantly reduced with ABC294640 treatment; however, dh-S1P was actually elevated in kidneys from LN mice treated with ABC294640. Together these data demonstrate a role for SKs in LN; however, they suggest that inhibition of SK1 or perhaps both SK isoforms would better prevent elevations in S1P and dh-S1P and potentially better protect against LN.

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“…In animal models of lupus nephritis, both FTY-720 and a specific S1P 1 receptor KRP-203 induced lymphopenia, reduced renal injury, and increased survival [47, 48]. A problem with this approach is that depending on the dose and frequency of its delivery, FTY-720 has been shown to induce and/or exacerbate vascular leak in the lung and brain [49, 50]; the mechanism by which FTY-720 can impair vascular integrity involves S1P 1 phosphorylation, internalization, and proteasomal degradation [33].…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1‐Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex–Induced Vascular Injury

Burg

Swendeman

Worgall

et al. 2018

Arthritis & Rheumatology

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FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice

Cited by 41 publications

References 24 publications

Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease

Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease

Inhibition of Sphingosine Kinase-2 in a Murine Model of Lupus Nephritis

Sphingosine 1‐Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex–Induced Vascular Injury

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