title: Denbinobin upregulates miR-146a expression and attenuates IL-1β-induced upregulation of ICAM-1 and VCAM-1 expressions in osteoarthritis fibroblast-like synoviocytes.
abstract: Interleukin-1β (IL-1β) upregulates intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions in osteoarthritis fibroblast-like synoviocytes (OA-FLS) via nuclear factor (NF)-κB-mediated mechanism; enhancement of leukocyte infiltration and upregulation of proinflammatory mediators play a crucial role in OA pathophysiology. MicroRNA (miR)-146a suppresses inflammatory responses by inhibiting NF-κB activity and target gene expression, and epigenetic mechanisms are reportedly involved in miR expression regulation. Here, we aimed to verify the inhibition of ICAM-1/VCAM-1 expression in OA-FLS on denbinobin treatment and to determine whether this inhibition was due to the miR-146a-dependent pathway. We also assessed the epigenetic regulation caused by histone acetyltransferases involved in denbinobin action. Denbinobin attenuated the upregulation of IL-1β-induced ICAM-1/VCAM-1 expression and monocyte adhesion to OA-FLS. The mechanism underlying the inhibitory effects of denbinobin involved miR-146a induction, which in turn inhibited NF-κB signaling. This is because miR-146a inhibitor abrogated the inhibitory effects of denbinobin. Furthermore, histone acetyltransferase inhibitor attenuated the denbinobin-induced upregulation of miR-146a expression and inhibited the acetylation of NF-κB-binding sites located within the miR-146a promoter region. These data suggest that an epigenetic mechanism plays a crucial role in the upregulation of miR-146a expression in response to denbinobin treatment. Our overall findings suggest that denbinobin can be used as a potent anti-inflammatory agent.
  
  
  CONCLUSIONS
  Denbinobin inhibited IL-1β-induced ICAM-1/VCAM-1 expression and monocyte adhesion to OA-FLS. It was due to denbinobin increased miR-146a level, which in turn inhibited NF-κB signaling. Our overall findings suggest that denbinobin can be used as a potent anti-inflammatory agent.
authors: School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei, Taiwan.
authors: Chia-Ron
authors: CR
authors: Yang
authors: Orthopedic Department, Shin Kong Wu Ho-Su Memorial Hospital, No. 95, Wenchang Road, Taipei, Taiwan.|School of Medicine, Fu-Jen Catholic University, No. 510, Zhongzheng Road, New Taipei City, Taiwan.|School of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, Taiwan.
authors: Kao-Shang
authors: KS
authors: Shih
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, Taiwan.
authors: Jing-Ping
authors: JP
authors: Liou
authors: Department of Orthopedic Surgery, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan.
authors: Yi-Wen
authors: YW
authors: Wu
authors: School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei, Taiwan.
authors: I-Ni
authors: IN
authors: Hsieh
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, Taiwan.
authors: Hsueh-Yun
authors: HY
authors: Lee
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, Taiwan.
authors: Tzu-Cheng
authors: TC
authors: Lin
authors: Department of Orthopedic Surgery, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan. jhwang@ntuh.gov.tw.
authors: Jyh-Horng
authors: JH
authors: Wang
mesh_terms: D000368:Aged; D000880:Anthraquinones / Q000737:chemistry*; D001665:Binding Sites; D002448:Cell Adhesion; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D035683:MicroRNAs / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D010329:Patella / Q000473:pathology; D010616:Phenanthrenes / Q000737:chemistry*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism; D000070918:Synoviocytes / Q000166:cytology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; C573420:ICAM1 protein, human; D053583:Interleukin-1beta; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D010616:Phenanthrenes; D019010:Vascular Cell Adhesion Molecule-1; C436544:denbinobin; D018799:Intercellular Adhesion Molecule-1
keywords: Denbinobin; ICAM-1; VCAM-1; miR-146a