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Regulation of COX-2 Expression and IL-6 Release by Particulate Matter in Airway Epithelial Cells

¹ Department of Medicine, University of Chicago, Chicago, Illinois; ² Department of Environmental Health Sciences, and ³ Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Viswanathan Natarajan, Ph.D., Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, Room W408B, 929 East 57th Street, Chicago, IL 60637. E-mail: vnataraj{at}medicine.bsd.uchicago.edu

Particulate matter (PM) in ambient air is a risk factor for human respiratory and cardiovascular diseases. The delivery of PM to airway epithelial cells has been linked to release of proinflammatory cytokines; however, the mechanisms of PM-induced inflammatory responses are not well-characterized. This study demonstrates that PM induces cyclooxygenase (COX)-2 expression and IL-6 release through both a reactive oxygen species (ROS)-dependent NF-B pathway and an ROS-independent C/EBPβ pathway in human bronchial epithelial cells (HBEpCs) in culture. Treatment of HBEpCs with Baltimore PM induced ROS production, COX-2 expression, and IL-6 release. Pretreatment with N-acetylcysteine (NAC) or EUK-134, in a dose-dependent manner, attenuated PM-induced ROS production, COX-2 expression, and IL-6 release. The PM-induced ROS was significantly of mitochondrial origin, as evidenced by increased oxidation of the mitochondrially targeted hydroethidine to hydroxyethidium by reaction with superoxide. Exposure of HBEpCs to PM stimulated phosphorylation of NF-B and C/EBPβ, while the NF-B inhibitor, Bay11–7082, or C/EBPβ siRNA attenuated PM-induced COX-2 expression and IL-6 release. Furthermore, NAC or EUK-134 attenuated PM-induced activation of NF-B; however, NAC or EUK-134 had no effect on phosphorylation of C/EBPβ. In addition, inhibition of COX-2 partly attenuated PM-induced Prostaglandin E2 and IL-6 release.

Key Words: ambient particulate matter • cytokine • reactive oxygen species • transcriptional factors • airway epithelium

CLINICAL RELEVANCE Particulate matter (PM) is a risk factor for human respiratory and cardiovascular diseases. Mechanisms linking PM-induced cyclooxygenase-2 expression and IL-6 secretion via mitochondrial reactive oxygen species (ROS)-dependent and ROS-independent pathways are provided.

 

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