Silica induces macrophage cytokines through phosphatidylcholine-specific phospholipase C with hydrogen peroxide.
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-alpha and IL-1beta 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-alpha and IL-1beta 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.
Liu
Honglei
H
School of Natural Sciences, University of California Merced, P.O. Box 2039, Merced, CA 95340, USA.
Zhang
Hongqiao
H
Forman
Henry Jay
HJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012822:Silicon Dioxide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*
D053583:Interleukin-1beta; D008665:Metalloporphyrins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012822:Silicon Dioxide; D006861:Hydrogen Peroxide; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D002118:Calcium