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Effects of Transforming Growth Factor-ß and Budesonide on Mitogen-Activated Protein Kinase Activation and Apoptosis in Airway Epithelial Cells

Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Catanzaro; and Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples, Italy

Address correspondence to: Dr. Girolamo Pelaia, M.D., Policlinico Universitario "Mater Domini," Via T. Campanella, 88100 Catanzaro, Italy. E-mail: pelaia{at}unicz.it

Airway epithelial cells play a central role in the inflammatory, apoptotic, and remodeling processes associated with asthma. Within this context, a key function is exerted by transforming growth factor-ß (TGF-ß), whose biological effects are mediated at least in part by mitogen-activated protein kinases (MAPKs). The aim of our study was to investigate, in primary cultures of human bronchial epithelial cells (HBEC), the effects of TGF-ß (10 ng/ml) on both MAPK activation and apoptosis, in the presence or absence of a pretreatment with budesonide (10^-8 M). MAPK activation was detected by Western blotting, using anti–phospho-MAPK monoclonal antibodies, which specifically recognize the phosphorylated, active forms of these enzymes. Apoptosis was assayed by caspase-3 activation and fluorescence microscopy, using annexin-V (An-V) and propidium iodide (PI) as markers of cell death. Our results show that TGF-ß induced a marked ( 9-fold) increase in p38 MAPK phosphorylation, and also dramatically enhanced cell death, which was completely prevented by specific MAPK inhibitors. Both MAPK activation and apoptosis were effectively inhibited by budesonide (BUD), thereby suggesting that the powerful antiapoptotic action of inhaled glucocorticoids may be very important for their protective role against epithelial injury, which represents a key pathogenic event in asthma.

Abbreviations: Annexin-V, An-V • budesonide, BUD • extracellular signal–regulated kinases, ERK • human bronchial epithelial cells, HBECs • c-Jun N-terminal kinases, JNK • mitogen-activated protein kinase, MAPK • propidium iodide, PI • sodium dodecyl sulfate, SDS • transforming growth factor-ß, TGF-ß

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