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Silica Induces Macrophage Cytokines through Phosphatidylcholine-Specific Phospholipase C with Hydrogen Peroxide

School of Natural Sciences, University of California Merced, Merced, California

Correspondence and requests for reprints should be addressed to Henry Jay Forman, School of Natural Sciences, University of California Merced, P.O. Box 2039, Merced, CA 95340. E-mail: hjforman{at}gmail.com

Silica particle–associated inflammation is implicated in the genesis of several pulmonary diseases, including silicosis and lung cancer. In this study we investigated the role of phosphatidylcholine-specific phospholipase C (PC-PLC) in silica-stimulated induction of TNF- and IL-1 and how PC-PLC activity is regulated by silica in a rat alveolar macrophage model. We demonstrated that inhibition of PC-PLC, which was achieved with tricychodecan-9-yl-xanthate (D609), blocked the silica-stimulated induction of TNF- and IL-1 in alveolar macrophage, suggesting that PC-PLC is involved in the silica-associated inflammatory response. PC-PLC activity was increased significantly by silica exposure, and this could be inhibited by MnTBAP, which catalyzes both the dismutation of O₂^.- to O₂ and H₂O₂ and the dismutation of H₂O₂ to O₂ and H₂O, revealing that PC-PLC activity is regulated in a redox-dependent manner. This is further confirmed by the finding that PC-PLC activity was increased by exogenous H₂O₂. The intracellular calcium chelator BAPTA blocked the H₂O₂-increased PC-PLC activity, while the calcium ionophore, A23187, enhanced PC-PLC activity. The data indicate that PC-PLC plays critical roles in the silica-associated inflammatory response and that PC-PLC is regulated through redox- and calcium-dependent manners in alveolar macrophages.

Key Words: phosphatidylcholine-specific phospholipase C • redox signaling • calcium • cytokine • hydrogen peroxide

CLINICAL RELEVANCE This study demonstrates that silica-induced production of hydrogen peroxide is essential to the activation of phosphatidylcholine specific phospholipase C in the mechanism of silica-induced cytokine induction in alveolar macrophages.