title: 25-Hydroxycholesterol enhances cytokine release and Toll-like receptor 3 response in airway epithelial cells.
abstract: BACKGROUND
  25-hydroxycholesterol (25-HC) is one of the oxysterols, which are oxidized derivatives of cholesterol, and has been reported to be involved in the pathogenesis of atherosclerosis and Alzheimer's disease. In lung, the possible involvement of 25-HC in airway diseases has been revealed. In the present study, we examined whether 25-HC affects the release of cytokines and also modulates the responses of toll-like receptor 3 (TLR3) in airway epithelial cells.
  
  
  METHODS
  The effect of 25-HC on the release of cytokines from primary human bronchial epithelial cells after stimulation with or without polyinosine-polycytidylic acid [poly(I:C)], a ligand for TLR3, and the signal transduction were examined.
  
  
  RESULTS
  25-HC significantly potentiated the release of interleukin-8 (IL-8) and IL-6 from the cells. This effect was more potent compared with that of other oxysterols, 22-HC and 27-HC. GW3965 and TO901317, synthetic agonists of liver X receptors that are receptors for oxysterols, did not augment the IL-8 release. 25-HC enhanced the nuclear factor-kappa B (NF-κB) DNA binding activity and translocation of phosphorylated c-Jun into the nucleus. The release of IL-8 was inhibited by the NF-κB inhibitor, caffeic acid phenethyl ester (CAPE), an inhibitor of nuclear factor kappa-B alpha (IκBα) inhibitor, BAY 11-7085, and an inhibitor of nuclear factor kappa-B kinase-2 (IKK-2) inhibitor, SC-514, but not by a c-Jun N-terminal kinase (JNK) inhibitory peptide, L-JNKi1. 25-HC significantly potentiated IL-8 release in poly(I:C)-treated cells and the augmentation was inhibited by CAPE, BAY 11-7085, and SC-514. Furthermore, 25-HC potentiated the translocation of interferon regulatory factor 3 into the nucleus and the release of interferon-beta (IFN-β) in poly(I:C)-treated cells.
  
  
  CONCLUSIONS
  These data demonstrated that 25-HC augments the release of IL-8 and IL-6 via NF-κB signalling pathway and enhances the release of IL-8 and IFN-β after stimulation of TLR3 in airway epithelial cells. 25-HC may be involved in the neutrophilic airway inflammation through the stimulant effect of IL-8 and IL-6 release and also potentiate the TLR3-mediated innate immunity in airway diseases.
authors: Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. koarai@wakayama-med.ac.jp
authors: Akira
authors: A
authors: Koarai
authors: Satoru
authors: S
authors: Yanagisawa
authors: Hisatoshi
authors: H
authors: Sugiura
authors: Tomohiro
authors: T
authors: Ichikawa
authors: Takashi
authors: T
authors: Kikuchi
authors: Kanako
authors: K
authors: Furukawa
authors: Keiichiro
authors: K
authors: Akamatsu
authors: Tsunahiko
authors: T
authors: Hirano
authors: Masanori
authors: M
authors: Nakanishi
authors: Kazuto
authors: K
authors: Matsunaga
authors: Yoshiaki
authors: Y
authors: Minakata
authors: Masakazu
authors: M
authors: Ichinose
mesh_terms: D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: C508606:CXCL8 protein, human; D006888:Hydroxycholesterols; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C007997:25-hydroxycholesterol