title: Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter.
abstract: Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe(-/-) mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe(-/-) mice or from Apoe(-/-) mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe(-/-) mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Tsinghua University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Chongxiu
authors.initials: C
authors.lastname: Sun
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Conglin
authors.initials: C
authors.lastname: Liu
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Shi
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aina
authors.initials: A
authors.lastname: He
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Huimei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Cardiology and Geriatrics, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: Departments of Cardiology and Geriatrics, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.affiliation: Departments of Cardiology and Geriatrics, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Shaunessy
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Sabina
authors.initials: S
authors.lastname: Jelen
authors.affiliation: Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bindels
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D018925:Chemokines / Q000378:metabolism; D002522:Chlorocebus aethiops; D020382:Interleukin-18 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D053724:Receptors, Interleukin-18 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D018925:Chemokines; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3