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25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway
Tomohiro Ichikawa1, Hisatoshi Sugiura, Akira Koarai
1Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8509, Japan.
Experimental Cell Research
|March 15, 2013
Summary
25-hydroxycholesterol (25-HC) promotes lung tissue remodeling in chronic airway diseases by increasing fibroblast activity. This occurs through a pathway involving nuclear factor-kappa B (NF-κB) and transforming growth factor-beta 1 (TGF-β1).
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Biochemistry
Background:
- Chronic airway diseases like COPD and asthma feature lung tissue remodeling, including fibrosis and alveolar destruction.
- 25-hydroxycholesterol (25-HC), produced by cholesterol 25-hydroxylase (CH25H) in macrophages, is implicated in arteriosclerosis.
- Increased CH25H expression and 25-HC production were observed in COPD lungs, but its role in lung remodeling remained unclear.
Purpose of the Study:
- To investigate the effect of 25-hydroxycholesterol (25-HC) on fibroblast-mediated lung tissue remodeling in vitro.
- To elucidate the molecular mechanisms underlying 25-HC's role in lung fibrosis.
Main Methods:
- Human fetal lung fibroblasts (HFL-1) were treated with 25-HC.
- Expression of alpha-smooth muscle actin (SMA) and collagen I were measured.
- Release and activation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were assessed.
- Transforming growth factor-beta 1 (TGF-β1) production was analyzed.
- Nuclear factor-kappa B (NF-κB) translocation and activator protein-1 (AP-1) activation were examined.
- Inhibitors and neutralizing antibodies for TGF-β and NF-κB pathways were used.
Main Results:
- 25-HC significantly increased alpha-smooth muscle actin (SMA) and collagen I expression in HFL-1 cells.
- 25-HC enhanced the release and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9, without affecting TIMP-1 or TIMP-2.
- 25-HC stimulated TGF-β1 production, and its effects were reversed by anti-TGF-β antibodies.
- 25-HC promoted NF-κB p65 nuclear translocation, but not phosphorylated c-jun (AP-1).
- Pharmacological inhibition of NF-κB reversed 25-HC-induced pro-fibrotic responses and TGF-β1 release.
Conclusions:
- 25-hydroxycholesterol (25-HC) promotes fibroblast-mediated lung tissue remodeling.
- 25-HC facilitates myofibroblast differentiation and excessive extracellular matrix protein and MMP release.
- These pro-fibrotic effects are mediated via an NF-κB and TGF-β1 dependent pathway.
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