The aryl hydrocarbon receptor (AhR) agonists may upregulate matrix metalloproteinases (MMPs) and contribute to many airway diseases, such as asthma and chronic obstructive pulmonary disease. Elucidation of the detailed molecular mechanisms regulating MMPs may provide the scientific basis for diagnostic and therapeutic opportunities to improve the care of various pulmonary diseases, especially those related to xenobiotic agents. In this study, we investigated the detailed mechanisms of how AhR agonists modulated the expressions and activities of MMPs in bronchial epithelial cells. Treating the cells (Beas-2B or HBE135-E6E7) with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester or 2,3,7,8-tetrachlorodibenzo-p-dioxin, we found these AhR agonists increased the expression and activity of MMP-1 via a noncanonical AhR pathway and increased the activity of MMP-2 and MMP-9 in an MMP-1-dependent manner. AhR agonists increased the expression of MMP-1 via the activation of mitogen-activated protein kinase (MAPK) pathways by increased cytosolic calcium level and activated calcium/calmodulin-dependent protein kinase II (CaMKII). The activated MAPK pathways phosphorylated c-Jun, c-Fos, and ATF-2, resulting in their nuclear translocation and binding to the activator protein-1 (AP-1) elements of the MMP-1 promoter region. These findings correlated clinically to the significantly higher plasma/serum MMP-1 level in asthmatic patients. In conclusion, the present study demonstrated a novel signaling pathway by which AhR agonists elevated intracellular calcium levels, which activated CaMKII, leading to increased MMP-1 expression through MAPK pathways in bronchial epithelial cell lines. This novel regulatory pathway may serve as a potential target for the treatment of airway remodeling of many pulmonary diseases, such as asthma.
AhR agonists increase MMP-1 expression in bronchial epithelial cells.
The underlying AhR pathway involves CaMKII, MAPKs, and AP-1 elements.
The upregulated MMP-1 further activated MMP-2 and MMP-9.
Asthmatic patients have higher serum MMP-1 level.
This novel regulatory pathway is a potential target for treating asthma.
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The authors thank the Center for Research Resources and Development at Kaohsiung Medical University for the instrumental support of confocal microscope. The authors also appreciate the careful review and precious comments from the editors and reviewers.
This study was supported by grants from the Kaohsiung Medical University Hospital (KMUH99-9I08, KMUH101-1M12 and KMUH102-2T06), National Science Council (NSC 101-2320-B-037-043-MY3) and National Health Research Institutes (NHRI-100A1-PDCO-03000001 and NHRI-101A1-PDCO-03010201).
Conflict of interest
The authors declare no conflicts of interest.
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Tsai, M., Hsu, Y., Wang, T. et al. Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity. J Mol Med 92, 615–628 (2014). https://doi.org/10.1007/s00109-014-1121-x
- Airway remodeling
- Aryl hydrocarbon receptor
- Chronic obstructive pulmonary disease
- Matrix metalloproteinase