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: Tomohiro Ichikawa, Hisatoshi Sugiura, Akira Koarai, Takashi Kikuchi, Masataka Hiramatsu, Hiroki Kawabata, Keiichiro Akamatsu, Tsunahiko Hirano, Masanori Nakanishi, Kazuto Matsunaga, Yoshiaki Minakata, Masakazu Ichinose
• Journal: Experimental cell research (Exp Cell Res) Vol. 319 Issue 8 Pg. 1176-86 (May 01 2013) ISSN: 1090-2422 [Electronic] United States
• PMID: 23485764 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Collagen Type I
• Hydroxycholesterols
• NF-kappa B
• 25-hydroxycholesterol
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Cell Differentiation (drug effects, genetics)
• Cells, Cultured
• Collagen Type I (metabolism)
• Fibroblasts (drug effects, metabolism, physiology)
• Fibrosis (chemically induced, genetics, metabolism)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Hydroxycholesterols (pharmacology)
• Lung (drug effects, metabolism, pathology)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Myofibroblasts (drug effects, metabolism, physiology)
• NF-kappa B (metabolism)
• Signal Transduction (drug effects, physiology)