Dysfunction of mitochondria and deformed gap junctions in the heart of IL-18-deficient mice.
Interleukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy.
Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan;
Wen
W
Li
Department of Pharmacology, Osaka Medical College, Osaka, Japan;
Denan
D
Jin
Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan;
Masaki
M
Hata
Department of Pharmacology, Osaka Medical College, Osaka, Japan;
Shinji
S
Takai
Department of Neuropsychiatry, Hyogo College of Medicine, Hyogo, Japan;
Kyosuke
K
Yamanishi
Shanghai Key Laboratory of Hypertension, Shanghai, China; and.
Weili
W
Shen
Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan;
Yosif
Y
El-Darawish
Hirakata General Hospital for Developmental Disorders, Osaka, Japan.
Hiromichi
H
Yamanishi
Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan; haruoka@hyo-med.ac.jp.
Haruki
H
Okamura
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004452:Echocardiography; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D017629:Gap Junctions / Q000648:ultrastructure*; D020382:Interleukin-18 / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010807:Physical Endurance; D017382:Reactive Oxygen Species / Q000378:metabolism; D013599:Systole; D015854:Up-Regulation
D018031:Connexin 43; C543076:GJA1 protein, mouse; D020382:Interleukin-18; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I
IL-18; cardiac myocytes; connexin 43; gap junction; mitochondrial autophagy