Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt–mTOR axis in mice

Hou, Huilian; Cao, Runjing; Sun, Yuchun; Liu, Xiaoqian; Song, Xiujuan; Guo, Li

doi:10.1016/j.intimp.2015.11.024

Cited by 28 publications

(21 citation statements)

References 38 publications

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“…Regarding its detailed mechanisms, other studies have discovered that FTY720 can promote PP2A phosphatase activities in many types of cells [30][31][32] and dephosphorylate activated signal transducer and activator of transcription-1 (STAT-3) [33,34] and AKT [35,36]. In our study, FTY720 reduced a-SMA and collagen expression, suggesting that FTY720 prevents the genesis of myofibroblasts and reduces the synthesis of ECM protein in vivo.…”

Section: Discussionsupporting

confidence: 54%

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Tian

Zhang

Zhu

et al. 2017

Clinical and Experimental Immunology

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Renal fibrosis is the common final manifestation of chronic kidney diseases and usually results in end-stage renal failure. In this study, we evaluated the effect of fingolimod (FTY720), an analogue of sphingosine 1-phosphate (S1P), as a treatment for the unilateral ureteral obstruction (UUO)-induced renal fibrosis animal model. We treated mice with FTY720 at a dosage of 1 mg/kg/day by intragastric administration from day 1 until day 7. The control group received the same amount of saline. FTY720 reduced significantly the urine albumin/creatinine ratio (UACR) in treated UUO mice. FTY720 treatment also caused a significant decrease in interstitial expansion and collagen deposition in the kidney, accompanied by reduced mononuclear cell recruitment and inflammatory cytokine expression. In addition, the expression levels of the endothelial cell adhesion molecules P-selectin and vascular cell adhesion protein 1 (VCAM-1) were suppressed in the ligated kidney by FTY720 administration, suggesting reduced renal endothelial cell activation. Furthermore, in renal interstitial fibroblast normal rat kidney (NRK)-49F cells, FTY720 significantly affected transforming growth factor (TGF)-β-induced α-smooth muscle actin (SMA) expression and collagen synthesis by inhibiting both the Mothers against decapentaplegic homologue (Smad)2/3 and phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K/AKT/GSK3β) signalling pathways. S1P1 knock-down by siRNA reversed this effect significantly in our fibroblast cell culture model. Therefore, FTY720 attenuates renal fibrosis via two different mechanisms: first, FTY720 suppresses the synthesis of extracellular matrix in interstitial fibroblasts by interfering with TGF-β signalling; and secondly, FTY720 affects endothelial cell activation and chemokine expression, thereby reducing immune cell recruitment into the kidney.

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Section: Discussionsupporting

confidence: 54%

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Tian

Zhang

Zhu

et al. 2017

Clinical and Experimental Immunology

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“…The main finding in our study is the observation that cells from EAE + Art mice presented lower expression of chemokine receptors, reduced migratory ability, and did not leave the secondary lymphoid organs in the course of EAE. Similar results are found in mice and transplanted/MS patients treated with FTY720 (fingolimod) and FK506 (tacrolimus) [46][47][48][49][50][51]. In our study, we found that T cells maintained their encephalitogenic potential after Art treatment, as transfer of cells from EAE + Art mice to RAG2 À/À mice resulted in normal disease development.…”

Section: Discussionsupporting

confidence: 88%

Artesunate Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Leukocyte Migration to the Central Nervous System

et al. 2016

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“…In a pattern different to that of IL‐10, mRNA levels for TGFB, already low in CIS individuals, were lower again in PBMCs from MS patients. Low levels of expression of tolerance‐inducing TGFB have been reported in experimental autoimmune encephalomyelitis, the murine model of neuroinflammation used to study MS, with increased expression after treatment with the disease modifier, fingolimod 23. Also, in PBMCs from patients with established disease, TNF mRNA levels are higher and IL‐10 and TGFB levels are lower during relapse, and this balance is inverted during stable disease 24…”

Section: Discussionmentioning

confidence: 99%

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

et al. 2018

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ObjectivesClinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS.MethodsAs immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum.ResultsWhen measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression.ConclusionHigher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression.

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Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt–mTOR axis in mice

Cited by 28 publications

References 38 publications

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Artesunate Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Leukocyte Migration to the Central Nervous System

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

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