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TGF-β Suppresses EGF-Induced MAPK Signaling and Proliferation in Asthmatic Epithelial Cells

¹ Centre de recherche de l'Hôpital Laval, Institut universitaire de cardiologie et de pneumologie, Sainte-Foy, Québec, Canada

Correspondence and requests for reprints should be addressed to Jamila Chakir, Ph.D., Centre de recherche, Hôpital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, PQ, G1V 4G5 Canada. E-mail: jamila.chakir{at}med.ulaval.ca

Epithelial damage is an important pathophysiologic feature of asthma. Bronchial epithelium damage results in release of growth factors such as transforming growth factor (TGF)-β₁ that may affect epithelial cell proliferation. The objective of our study is to evaluate the importance of TGF-β₁ in regulating epithelial cell repair in asthma. We evaluated the effect of TGF-β₁ on epidermal growth factor (EGF)-induced proliferation and downstream signaling in epithelial cells obtained from subjects with asthma compared with cells from healthy subjects. Cell proliferation was evaluated by bromodeoxyuridine incorporation. EGF receptor (EGFR), mitogen-activated protein kinase, TGF-β receptors, Smads, Smad anchor for receptor activation (SARA), and cyclin-dependant kinase inhibitors were evaluated by Western blot. TGF-β₁ and receptor expression were measured by RT-PCR and by enzyme-linked immunosorbent assay. Proliferation of epithelial cells at baseline and after EGF stimulation was significantly reduced in cells derived from subjects with asthma compared with cells obtained from healthy control subjects. EGF-induced ERK1/2 phosphorylation was reduced in epithelial cells from subjects with asthma compared with cells from healthy control subjects. This was paralleled with a reduced EGFR phosphorylation. Addition of TGF-β₁ significantly decreased EGF-induced cell proliferation. TGF-β₁ production was higher in asthmatic epithelial cells compared with normal cells. This was supported by a high expression of pSmad 3 and SARA in cells derived from individuals with asthma compared with normal subjects. Cycline-dependent kinase inhibitors were highly expressed in asthmatic compared with normal cells. Inhibition of TGF-β₁ signaling in asthmatic epithelial cells restored EGFR, ERK1/2 phosphorylation, and cell proliferation induced by EGF. Our results suggest that TGF-β restrains EGFR phosphorylation and downstream signaling in bronchial epithelial cells.

Key Words: asthma • epithelial cell • proliferation • EGF receptor • TGF-β₁ receptors

CLINICAL RELEVANCE Epithelial cell repair is dependent on the capacity of the cell to proliferate. Development of new strategies that will specifically target transforming growth factor-β could be useful to help repair airway epithelium in asthma.

 

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