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Quercetin Blocks Airway Epithelial Cell Chemokine Expression

Departments of Pediatrics and Communicable Diseases, Molecular and Integrative Physiology, Family Medicine and Pathology, University of Michigan, Ann Arbor, Michigan; and Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana

Correspondence and requests for reprints should be addressed to Marc B. Hershenson, University of Michigan, 1150 W. Medical Center Drive, Box 0688, Ann Arbor, MI 48109–0688. E-mail: mhershen{at}umich.edu

Quercetin (3,3',4',5,7-pentahydroxyflavone), a dietary flavonoid, is an inhibitor of phosphatidylinositol (PI) 3-kinase and potent antioxidant. We hypothesized that quercetin blocks airway epithelial cell chemokine expression via PI 3-kinase–dependent mechanisms. Pretreatment with quercetin and the PI 3–kinase inhibitor LY294002 each reduced TNF-–induced IL-8 and monocyte chemoattractant protein (MCP)-1 (also called CCL2) expression in cultured human airway epithelial cells. Quercetin also inhibited TNF-–induced PI 3-kinase activity, Akt phosphorylation, intracellular H₂O₂ production, NF-B transactivation, IL-8 promoter activity, and steady-state mRNA levels, consistent with the notion that quercetin inhibits chemokine expression by attenuating NF-B transactivation via a PI 3-kinase/Akt-dependent pathway. Quercetin also reduced TNF-–induced chemokine secretion in the presence of the transcriptional inhibitor actinomycin D, while inducing phosphorylation of eukaryotic translation initiation factor (eIF)-2, suggesting that quercetin attenuates chemokine expression by post-transcriptional as well as transcriptional mechanisms. Finally, we tested the effects of quercetin in cockroach antigen–sensitized and –challenged mice. These mice show MCP-1–dependent airways hyperresponsiveness and inflammation. Quercetin significantly reduced lung MCP-1 and methacholine responsiveness. We conclude that quercetin blocks airway cell chemokine expression via transcriptional and post-transcriptional pathways.

Key Words: asthma • chemokines • epithelial cells • lung • signal transduction