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p38 and EGF receptor kinase-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway is required for Zn²⁺-induced cyclooxygenase-2 expression

¹Division of Immunology and Infectious Disease, Department of Pediatrics, ²Center for Environmental Medicine, Asthma, and Lung Biology, ⁴Department of Medicine and Lineberger Comprehensive Cancer Center, and ⁵Department of Pharmacology, University of North Carolina, Chapel Hill; and ³Human Studies Division, National Health Effects and Environmental Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina

Submitted 29 April 2005 ; accepted in final form 22 June 2005

Cyclooxygenase 2 (COX-2) expression is induced by physiological and inflammatory stimuli. Regulation of COX-2 expression is stimulus and cell type specific. Exposure to Zn²⁺ has been associated with activation of multiple intracellular signaling pathways as well as the induction of COX-2 expression. This study aims to elucidate the role of intracellular signaling pathways in Zn²⁺-induced COX-2 expression in human bronchial epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) potently block Zn²⁺-induced COX-2 mRNA and protein expression. Overexpression of adenoviral constructs encoding dominant-negative Akt kinase downstream of PI3K or wild-type phosphatase and tensin homolog deleted on chromosome 10, an important PI3K phosphatase, suppresses COX-2 mRNA expression induced by Zn²⁺. Zn²⁺ exposure induces phosphorylation of the tyrosine kinases, including Src and EGF receptor (EGFR), and the p38 mitogen-activated protein kinase. Blockage of these kinases results in inhibition of Zn²⁺-induced Akt phosphorylation as well as COX-2 protein expression. Overexpression of dominant negative p38 constructs suppresses Zn²⁺-induced increase in COX-2 promoter activity. In contrast, the c-Jun NH₂-terminal kinase and the extracellular signal-regulated kinases have minimal effect on Akt phosphorylation and COX-2 expression. Inhibition of p38, Src, and EGFR kinases with pharmacological inhibitors markedly reduces Akt phosphorylation induced by Zn²⁺. However, the PI3K inhibitors do not show inhibitory effects on p38, Src, and EGFR. These data suggest that p38 and EGFR kinase-mediated Akt activation is required for Zn²⁺-induced COX-2 expression and that the PI3K/Akt signaling pathway plays a central role in this event.

zinc; airway epithelial cell; signal transduction

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