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Induction and regulation of matrix metalloproteinase-12 in human airway smooth muscle cells.

Abstract：

BACKGROUND:The elastolytic enzyme matrix metalloproteinase (MMP)-12 has been implicated in the development of airway inflammation and remodeling. We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases. METHODS:Laser capture microdissection was used to collect smooth muscle cells from human bronchial biopsy sections. MMP-12 mRNA expression was analysed by quantitative real-time RT-PCR. MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot. MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry. MMP-12 activity was determined by zymography. The TransAM AP-1 family kit was used to measure c-Jun activation and nuclear binding. Analysis of variance was used to determine statistical significance. RESULTS:We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough. The pro-inflammatory cytokine, interleukin (IL)-1beta, induced a >100-fold increase in MMP-12 gene expression and a >10-fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures. Selective inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphatidylinositol 3-kinase reduced the activity of IL-1beta on MMP-12, indicating a role for these kinases in IL-1beta-induced induction and release of MMP-12. IL-1beta-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-alpha through enhancing activator protein-1 activation by IL-1beta. Transforming growth factor-beta had no significant effect on MMP-12 induction. CONCLUSION:Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1beta and TNF-alpha. Bronchial smooth muscle cells may be an important source of elastolytic activity, thereby participating in remodeling in airway diseases such as COPD and chronic asthma.

journal_name

Respir Res

journal_title

Respiratory research

authors

Xie S,Issa R,Sukkar MB,Oltmanns U,Bhavsar PK,Papi A,Caramori G,Adcock I,Chung KF

doi

10.1186/1465-9921-6-148

keywords:

subject

Has Abstract

pub_date

2005-12-16 00:00:00

pages

148

eissn

1465-9921

issn

1465-993X

pii

1465-9921-6-148

journal_volume

pub_type

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Induction and regulation of matrix metalloproteinase-12 in human airway smooth muscle cells.