title: Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, reduces chemokines and adhesion molecule expression induced by IL-1β in human corneal fibroblasts.
abstract: OBJECTIVE
  Dehydroxymethylepoxyquinomicin (DHMEQ) is derived from the antibiotic, epoxyquinomicin C, and is a novel low molecular weight nuclear factor-κB (NF-κB) inhibitor. We investigated the effects of DHMEQ on the expression of chemokines and the intercellular adhesion molecule (ICAM)-1 induced by proinflammatory cytokines in cultures of the human corneal fibroblasts (HCFs).
  
  
  METHODS
  The cytotoxicity of DHMEQ on cultured HCFs was evaluated by cell proliferation assays. Cultures were exposed to interleukin (IL)-1β, and the production of IL-8 and monocyte chemoattractant protein (MCP)-1 was assessed by enzyme-linked immunosorbent assay. The degree of expression of ICAM-1 was measured by flow cytometry. The translocation of NF-κB p65 into the nucleus of HCFs was assessed by immunocytochemistry.
  
  
  RESULTS
  DHMEQ was not toxic to cultured HCFs at doses up to 10 μg/ml. DHMEQ significantly suppressed the production of both IL-8 and MCP-1 in IL-1β-stimulated HCFs. In addition, DHMEQ down-regulated ICAM-1 expression in IL-1β-stimulated HCFs in a dose-dependent manner. DHMEQ inhibited the IL-1β-induced nuclear accumulation of p65, a component of NF-κB, in HCFs.
  
  
  CONCLUSIONS
  The suppression of inflammatory chemokines IL-8 and MCP-1 and inhibition of the expression of ICAM-1 in cultured HCFs by DHMEQ indicates that DHMEQ may have a therapeutic potential for treating ICAM-1 and chemokine-mediated corneal inflammatory disorders.
authors.affiliation: Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Inokawa
authors.forename: Takayo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Keino
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Akito
authors.initials: A
authors.lastname: Hirakata
authors.forename: Annabelle A
authors.initials: AA
authors.lastname: Okada
authors.forename: Ken
authors.initials: K
authors.lastname: Fukuda
authors.forename: Atsuki
authors.initials: A
authors.lastname: Fukushima
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D060527:Corneal Keratocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003512:Cyclohexanones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D001549:Benzamides; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D003512:Cyclohexanones; C573420:ICAM1 protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin; D018799:Intercellular Adhesion Molecule-1