Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)i...Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.展开更多
Our previous study has demonsstrated that donor specific graft tolerance can be induced by donor spleen cells from dexamethasone (DEX ) triated rats (DEX SPC). In this study we investigated if FTY 720. a new immunosup...Our previous study has demonsstrated that donor specific graft tolerance can be induced by donor spleen cells from dexamethasone (DEX ) triated rats (DEX SPC). In this study we investigated if FTY 720. a new immunosuppressant. could have a synergistic effect with DEX -SPC on the tolerance inductivity. The results showed that graft survival was further prolonged in reedients receiving both preoperative higher dose (10 mg/kg daily ) FTY 720 and DEX-SPC. However. the preoperative low dose (1 mg /kg daily ) FTY 720 did not show any syner gistic effect on tolerance induction with DEX -SPC. Unexpectedly in the perioperative regimen the lower dose FTY 720 had a synergistic effect with DEX -SPC. while the higher dose did not have. in prolonging graft survival. It is indicated that FTY 720 synergistically helps DEX-SPC to induce tolerance .The results also reinforce the viewpoint that the fortune of an allograft. tolerallced or rejected id not determjned by the nature of donor antigen, but is the function of antigen presentation and recipient T cells . Furthermore . the authors also proposed ’the way and frequency of antigen presentation model ’to interpret the apparently paradoxical results .展开更多
Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyeliti...Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.展开更多
Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involve...Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.展开更多
基金supported by grants from the National Natural Science Foundation of China,No.81971231(to JL)Liaoning Revitalization Talents Program,No.XLYC1907178(to JL)。
文摘Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.
文摘Our previous study has demonsstrated that donor specific graft tolerance can be induced by donor spleen cells from dexamethasone (DEX ) triated rats (DEX SPC). In this study we investigated if FTY 720. a new immunosuppressant. could have a synergistic effect with DEX -SPC on the tolerance inductivity. The results showed that graft survival was further prolonged in reedients receiving both preoperative higher dose (10 mg/kg daily ) FTY 720 and DEX-SPC. However. the preoperative low dose (1 mg /kg daily ) FTY 720 did not show any syner gistic effect on tolerance induction with DEX -SPC. Unexpectedly in the perioperative regimen the lower dose FTY 720 had a synergistic effect with DEX -SPC. while the higher dose did not have. in prolonging graft survival. It is indicated that FTY 720 synergistically helps DEX-SPC to induce tolerance .The results also reinforce the viewpoint that the fortune of an allograft. tolerallced or rejected id not determjned by the nature of donor antigen, but is the function of antigen presentation and recipient T cells . Furthermore . the authors also proposed ’the way and frequency of antigen presentation model ’to interpret the apparently paradoxical results .
文摘Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.
文摘Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.
