title: Endothelin regulates function of IL-17-producing T cell subset.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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: 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.
authors: Kensuke
authors: K
authors: Tanaka
authors: Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan.
authors: Kento
authors: K
authors: Yoshioka
authors: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Koichiro
authors: K
authors: Tatsumi
authors: Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan.
authors: Sadao
authors: S
authors: Kimura
authors: Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan. Electronic address: kasuya@faculty.chiba-u.jp.
authors: Yoshitoshi
authors: Y
authors: Kasuya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010456:Peptides, Cyclic / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: ET-1; IL-17; Multiple sclerosis; Th17