FTY720抑制TLR4信号转导的炎症反应  

FTY720 inhibitis inflammatory response by down-regulation of TLR4 signaling

作　　者：王伟[1] 秦晓黎[1] 王文静[1] 林羿[1] 

机构地区：[1]上海交通大学医学院附属仁济医院药剂科,上海200127

出　　处：《现代免疫学》2012年第2期89-93,共5页Current Immunology

基　　金：国家自然科学基金资助项目(31171439)

摘　　要：FTY720是一种1-磷酸神经鞘氨醇(sphingosine 1-phosphate,S1P)受体拮抗剂。为阐明FTY720抑制炎症反应的机理,本研究采用流式细胞术检测FTY720对细菌脂多糖(LPS)刺激后小鼠脾脏细胞TLR4表达水平的影响。研究发现,注射适当剂量的FTY720可削弱LPS所引起的TLR4表达水平增强(FTY720处理组与对照组相比,TLR4+细胞构成比分别为6.7%±1.5%和38.6%±3.1%,P<0.01),并可消除LPS刺激所引起的外周血TNF-α、IFN-γ和IL-12等Th1型细胞因子表达水平增高(FTY720组血清TNF-α、IFN-γ和IL-12浓度分别为(72±22)ng/ml、(46±21)ng/ml和(19±4)ng/ml,LPS组分别为(300±75)ng/ml、(175±35)ng/ml和(50±8)ng/ml,均为P<0.01)。相反,FTY720组血清Th2型细胞因子IL-4水平与对照组相比分别为(7±3)ng/ml和(7±2)ng/ml,无显著性差异。在体外细胞培养实验中可观察到一致的结果。这些发现提示,FTY720可能通过抑制LPS/TLR4信息转导通路,下调TNF-α、IFN-γ和IL-12等Th1型细胞因子表达而抑制炎症反应。FTY720 （2-amino-2-E2-（4-octylphenyl）ethyl]propane-I, 3-diol） is known to be an agonist of sphingosine 1-phos- phate （S1P） receptor. To make clear the mechanism by which FTY720 inhibits inflamation, flow cytometry was performed to determine the effect of FTY720 on LPS-indueed up-regulation of TLR4 in murine spleen cells in this study. It showed that ade- quate dosage of FTY720 abrogated LPS-induced TLR4 expression. The proportion of TLR4＋ cells was 6. 7%± 1. 5% in FTY720-treated group, significantly lower than that in the control group （38.6 % ± 3.1 ; P〈0.01）. Subsequently, up-regulated expression of Thl-type cytokines, including TNF-α, IFN-γ and IL-12, in response to LPS stimulation was abrogated by FTY720 administration. Serum level of TNF-α, IFN-γ, and IL-12 were （72±22）ng/ml, （46±21）ng/ml, and （19±4）ng/ml respectively in FTY720 group, significantly lower than that in the control group [（300±75）ng/ml, （175±35）ng/ml, and （50±8） ng/ml, respectively; P〈0.01 for all]. In contrast, no significant difference was observed in the serum level of Th2 type cytokine IL-4 （7 3 ng/ml in the FTY720-treated group and 7 2 ng/ml in LPS-treated group）. A similar trend was observed in in vitro cell culture systems. These results suggest that FTY720 may inhibit LPS/TLR4 pathway, down-regulate Thl type ey- tokine expression, and modulate inflammatory response.

关 键 词：动物模型 细胞信息转导 免疫调节 炎症 

分 类 号：R915[医药卫生—微生物与生化药学]