Kensuke Tanaka1, Kento Yoshioka2, Koichiro Tatsumi3, Sadao Kimura2, Yoshitoshi Kasuya4. 1. Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan; Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. 2. Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan. 3. Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. 4. Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan. Electronic address: kasuya@faculty.chiba-u.jp.
Abstract
AIMS: Although endothelin (ET) is known to play pleiotropic roles in various pathological conditions, its relation to autoimmune disease has not been elucidated. Here, we focused on interleukin (IL)-17, which is closely related to the pathogenesis of multiple sclerosis, and investigated the effect of ET receptor blockers on the production of IL-17 by T lymphocytes. MAIN METHODS: Lymph node cells from mice at 8 days post-immunization with MOG35-55 were stimulated in vitro with MOG35-55 in the presence or absence of an ET receptor blocker (BQ123 for ETA or BQ788 for ETB). Naïve T cells from mice were subjected to an in vitro model of Th17 differentiation, and ET-mediated IL-17 production was investigated under the states of Th17 differentiation and activation. KEY FINDINGS: ELISA revealed that MOG35-55-induced IL-17 production was significantly inhibited by BQ123 but not BQ788. Consistent with the ELISA results for IL-17, the frequency of CD4(+) T cells producing IL-17 but not IFN-γ was reduced by BQ123. Under the differentiating state from naïve T cells to Th17 cells, the spontaneous release of IL-17 from CD4(+) T cells was increased, which was insensitive to BQ123, indicating that ET/ETA signaling did not affect Th17 differentiation. After the time period of Th17 differentiation, however, the increase in IL-17 production by restimulation of the cells with anti-CD3 plus anti-CD28 antibodies was significantly inhibited by BQ123. SIGNIFICANCE: We demonstrated that ET/ETA signaling plays a crucial role in IL-17 production by Th17. BQ123 might be expected to be a future therapeutic drug for multiple sclerosis.
AIMS: Although endothelin (ET) is known to play pleiotropic roles in various pathological conditions, its relation to autoimmune disease has not been elucidated. Here, we focused on interleukin (IL)-17, which is closely related to the pathogenesis of multiple sclerosis, and investigated the effect of ET receptor blockers on the production of IL-17 by T lymphocytes. MAIN METHODS: Lymph node cells from mice at 8 days post-immunization with MOG35-55 were stimulated in vitro with MOG35-55 in the presence or absence of an ET receptor blocker (BQ123 for ETA or BQ788 for ETB). Naïve T cells from mice were subjected to an in vitro model of Th17 differentiation, and ET-mediated IL-17 production was investigated under the states of Th17 differentiation and activation. KEY FINDINGS: ELISA revealed that MOG35-55-induced IL-17 production was significantly inhibited by BQ123 but not BQ788. Consistent with the ELISA results for IL-17, the frequency of CD4(+) T cells producing IL-17 but not IFN-γ was reduced by BQ123. Under the differentiating state from naïve T cells to Th17 cells, the spontaneous release of IL-17 from CD4(+) T cells was increased, which was insensitive to BQ123, indicating that ET/ETA signaling did not affect Th17 differentiation. After the time period of Th17 differentiation, however, the increase in IL-17 production by restimulation of the cells with anti-CD3 plus anti-CD28 antibodies was significantly inhibited by BQ123. SIGNIFICANCE: We demonstrated that ET/ETA signaling plays a crucial role in IL-17 production by Th17. BQ123 might be expected to be a future therapeutic drug for multiple sclerosis.
Authors: Tabata M Dos Santos; Renato F Righetti; Bianca G Rezende; Elaine C Campos; Leandro do N Camargo; Beatriz M Saraiva-Romanholo; Silvia Fukuzaki; Carla M Prado; Edna A Leick; Milton A Martins; Iolanda F L C Tibério Journal: Ther Adv Respir Dis Date: 2020 Jan-Dec Impact factor: 4.031