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[2016.06] Alleviation of collagen-induced arthritis by the benzoxathiole derivative BOT-4-one in mice: Implication of theTh1- and Th17-cell-mediated immune resp
2016/06/24

 2016 Jun 15;110-111:47-57. doi: 10.1016/j.bcp.2016.03.018. Epub 2016 Mar 19.

Alleviation of collagen-induced arthritis by the benzoxathiole derivative BOT-4-one in miceImplication of theTh1- and Th17-cell-mediated immune responses.

Author information

  • 1Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21(PLUS)), Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 2Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 3Department of Health & Aesthetic Science, Gyeongbuk Provincial College, Yecheon, Republic of Korea.
  • 4Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 5Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 6Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 7Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
  • 8Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
  • 9Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea; Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea. Electronic address: wonwoolee@snu.ac.kr.
  • 10Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21(PLUS)), Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: sangkyu@snu.ac.kr.

Abstract

Autoimmune rheumatoid arthritis is characterized by chronic inflammation and hyperplasia in the synovial joints. Although the cause of rheumatoid arthritis is largely unknown, substantial evidence has supported the importance of immune cells and inflammatory cytokines in the initiation and progression of this disease. Herein, we demonstrated that the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) alleviated type II collagen-induced arthritis in a mouse model. The levels of pro-inflammatory cytokines are elevated in both human patients with rheumatoid arthritis and mice with collagen-induced arthritisBOT-4-one treatment reduced the levels of pro-inflammatory cytokines in mice and endotoxin-stimulated macrophages. BOT-4-one treatment suppressed the polarization of Th1- and Th17-cell subsets by inhibiting the expression and production of their lineage-specific master transcription factors and cytokines, as well as activation of signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited mitogen-activated protein kinase and NF-kappaB signaling as well as the transcriptional activities and DNA-binding of transcription factors, including activator protein-1, cAMP response element-binding protein and NF-kappaB. Our results suggest that BOT-4-one may have therapeutic potential for the treatment of chronic inflammation associated with autoimmune rheumatoid arthritis.

Copyright © 2016 Elsevier Inc. All rights reserved.

KEYWORDS:

2-Cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one); Mitogen-activated protein kinase (MAPK); NF-kappaB (NF-κB); Rheumatoid arthritis; Signal transducer and activator of transcription (STAT) 

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