title: Alleviation of collagen-induced arthritis by the benzoxathiole derivative BOT-4-one in mice: Implication of the Th1- and Th17-cell-mediated immune responses.
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 arthritis. BOT-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.
authors.affiliation: Department 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.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department 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.
authors.forename: Bo Ruem
authors.initials: BR
authors.lastname: Yoon
authors.affiliation: Department of Health & Aesthetic Science, Gyeongbuk Provincial College, Yecheon, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department 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.
authors.forename: Kum Hee
authors.initials: KH
authors.lastname: Noh
authors.affiliation: Department 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.
authors.forename: Sun-Ho
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department 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.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Yi
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Health & Aesthetic Science, Gyeongbuk Provincial College, Yecheon, Republic of Korea.
authors.forename: Jung Sook
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.affiliation: Department 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.
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.affiliation: Department 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.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: C561472:2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo(1,3)oxathiol-4-one; D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017362:Cyclic AMP Response Element-Binding Protein; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C577686:interleukin-6, mouse; D020928:Mitogen-Activated Protein Kinases
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)