title: 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway.
abstract: Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblasts (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-β1 production (P<0.01) and a neutralizing anti-TGF-β antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-β1 release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-β dependent pathway.
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Akira
authors.initials: A
authors.lastname: Koarai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Masataka
authors.initials: M
authors.lastname: Hiramatsu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawabata
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Akamatsu
authors.forename: Tsunahiko
authors.initials: T
authors.lastname: Hirano
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Minakata
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D024042:Collagen Type I; D006888:Hydroxycholesterols; D016328:NF-kappa B; C007997:25-hydroxycholesterol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9