IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death
Masashi Sada, Shouji Matsushima, Masataka Ikeda, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Hiroko Deguchi Miyamoto, Yoshitomo Tsutsui, Ryo Miyake, Daiki Setoyama, Dongchon Kang, Tomomi Ide, Hiroyuki Tsutsui
Abstract
Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.