Aryl hydrocarbon receptor signaling promotes ORMDL3- dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase  

作　　者：Hsueh-Chun Wang Tzu-Hsuan Wong Li-Ting Wang Hsiang-Han Su Hsiu-Yueh Yu Ai-Hsuan Wu Yu-Chun Lin Hua-Ling Chen Jau-Ling Suen Shih-Hsien Hsu Li-Chen Chen Yufeng Zhou Shau-Ku Huang 

机构地区：[1]Department of Medical Research,China Medical University Hospital,China Medical University,40402 Taichung,Taiwan,China [2]Graduate Institute of Medicine,College of Medicine,Kaohsiung Medical University,Kaohsiung,Taiwan,China [3]Division of Allergy,Asthma and Rheumatology,Department of Pediatrics,Chang Gung Memorial Hospital,Taoyuan,Taiwan,China [4]National Institute of Environmental Health Sciences,National Health Research Institutes,Miaoli,Taiwan,China [5]Research Center of Environmental Medicine,Kaohsiung Medical University,Kaohsiung,Taiwan,China [6]Center for Research Resources and Development,Kaohsiung Medical University,Kaohsiung,Taiwan,China [7]Community Medicine Research Center,Chang Gung Memorial Hospital at Keelung,Keelung,Taiwan,China [8]Department of Pediatrics,Xiamen Chang Gung Hospital,Xiamen,China [9]Johns Hopkins University School of Medicine,Baltimore,MD,USA [10]Key Laboratory of Neonatal Disease,Children’s Hospital and Institute of Biomedical Sciences,Ministry of Health,Fudan University,201102 Shanghai,China [11]Lou-Hu Hospital,Shen-Zhen University,Shen-Zhen,China

出　　处：《Cellular & Molecular Immunology》2019年第10期783-790,共8页中国免疫学杂志（英文版）

基　　金：This work was supported,in part,by grants from the National Health Research Institutes,Taiwan(EOPP10-014 and EOSP07-014 to S.-K.H.);Kaohsiung Medical University“The Talent Plan”(105KMUOR04 to S.-K.H.);the Ministry of Science and Technology,Taiwan(MOST 105-2320-B-039-004 and MOST 106-2320-B-039-037,to H.-C.W.);China Medical University Hospital,Taiwan(DMR-106-154 and DMR-107-117,to H.-C.W.);the Community Medicine Research Center,Chang Gung Memorial Hospital at Keelung(CMRPG3E1183 to L.-C.C.);the 1000 Young Talents Plan Program,China(to Y.Z.);the Initial Funding for New PI,Fudan Children’s Hospital and Fudan University(to Y.Z.);the National Natural Science Foundation of China(81671561,to Y.Z.);the National Key Research and Development Program of China(2016YFC1305102,to Y.Z.)。

摘　　要：Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.

关 键 词：Aryl hydrocarbon receptor ORMDL sphingolipid biosynthesis regulator 3 Sphingosine-1-phosphate Sphingosine-1-phosphate lyase 

分 类 号：O62[理学—有机化学]