Interleukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a pro-inflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in non-immune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient (IL-18KO) mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18 KO mice ran significantly shorter distances compared to 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 discs, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphologic observation, mitochondrial respiratory function, including that of Complex 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 up-regulated 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 pro-inflammatory 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.
- mitochondrial autophagy
- cardiac myocytes
- gap junction
- connexin 43
- Copyright © 2016, American Journal of Physiology - Heart and Circulatory Physiology