Blockage of sphingosine-1-phosphate receptor 2 attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice  

作　　者：Soo-Jin Park Dong-Soon Im 

机构地区：[1]College of Pharmacy,Pusan National University,Busan 46241,Republic of Korea [2]Laboratory of Pharmacology,College of Pharmacy,and Department of Life Nanopharmaceutical Sciences,Graduate School,Kyung Hee University,Seoul 02447,Republic of Korea

出　　处：《Acta Pharmacologica Sinica》2020年第11期1487-1496,共10页中国药理学报（英文版）

基　　金：supported by the Basic Science Research Program of the Korean National Research Foundation funded by the Korean Ministry of Education,Science and Technology(NRF-2019R1A2C1005523).

摘　　要：Sphingosine-1-phosphate(S1P)and its receptors have been implicated in functions of Langerhans cells and atopic dermatitis.In thisstudy,we investigated the roles of S1P receptor type 2(S1P2)in a mouse model of atopic dermatits,which was induced by topicalapplication of 2,4-dinitrochlorobenzene(DNCB)on ventral skin on D0,followed by repeated DNCB challenge on both ears from D7 to D49.wld-type mice with atopic dermatitis displayed severe inflammation and mast cell accumulation in ear tssues and elevated lgElevels in serum.Furthermore,the mice showed significantly increased sizes of draining lymph nodes,high levels of inflammatorycytokines(IL-4,IL-13,IL-17,and IFN-γ)in the ears and lymph nodes and high levels of chemokines CCL17 and CCL 22 in ears.Administration of JTE-013,a selective antagonist of S1P2(3 mg·kg,ip,from D19 to D49)before DNCB challenge significantly suppressedDNCB-induced atopic responses in ears and lymph nodes.JTE-013 administration aso significantly decreased the lymph nodes sizes,the levels of inflammatory cytokines(IL-4,IL-13,IL-17,and IFN-γ)in the ears and lymph nodes,and the levels of chemokines CCL17 andCCL22 in ears.Furthermore,the infammatory responses of atopic dermatitis were greatly ameliorated in S1pr2 gene-dehicient mice.As CCL17 and CCL22 are CCR4 ligands,acting as Th2-attracting chemokines,we investigated CCL17 and CCl22 expression in bonemarow-derived denditic cells(BMDCs)from wild-type and S1pr2 gene-deficient mice.Addition of IL-4(10ng/mL)markedly increasedthe levels of CCL17 and CC122,butlLl-4-induced CCL17 and CCcL22 expression was significanty blunted in BMDCcs from S1pr2 genedeficient mice.Furthermore,pretreatment with JTE-013(1-30μM)dose-dependenty suppressed this induction in BMDCs from wild-type mice.Our results demonstrate that blockage of S1P2 ameliorates not only DNCB-induced atopic dermatitis symptoms but also Th2 cell-attracting capacity of dendritic cells,suggesting S1P2 as a potential therapeutic target for atopic dermatitis.

关 键 词：atopic dermatitis sphingosine-1-phosphate sphingosine-1-phosphate receptor type 2(S1P2) S1pr2 gene-deficient mice bone marrow-derived dendritic cell cytokines 

分 类 号：R91[医药卫生—药学] R75