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Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter
- Source :
- Nature Medicine, 21, 7, pp. 820-6, Nature Medicine, 21, 820-6, Nature medicine
- Publication Year :
- 2015
-
Abstract
- Item does not contain fulltext 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. 01 juli 2015
- Subjects :
- Apolipoprotein E
Cell signaling
medicine.medical_specialty
Chemokine
medicine.medical_treatment
Biology
General Biochemistry, Genetics and Molecular Biology
Article
Mice
Apolipoproteins E
Internal medicine
Chlorocebus aethiops
parasitic diseases
medicine
Animals
Solute Carrier Family 12, Member 3
Receptor
Aorta
Receptors, Interleukin-18
urogenital system
Macrophages
Interleukin-18
General Medicine
Atherosclerosis
Molecular biology
Interleukin-18 receptor
Cytokine
Endocrinology
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
COS Cells
embryonic structures
biology.protein
Interleukin 18
Signal transduction
Chemokines
Tunica Intima
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 10788956
- Database :
- OpenAIRE
- Journal :
- Nature Medicine, 21, 7, pp. 820-6, Nature Medicine, 21, 820-6, Nature medicine
- Accession number :
- edsair.doi.dedup.....96f67b8c6ce46997ee4a1969cbf3d38b