title: Iron-mediated lipid peroxidation and lipid raft disruption in low-dose silica-induced macrophage cytokine production.
abstract: Silica inhalation can induce respiratory disease. Iron is suspected of playing an important role in silica-mediated respiratory toxicity, but unambiguously determining its role has been hampered by incomplete characterization, use of high particle doses, and lack of understanding of proinflammatory mechanisms. In this study, we investigated a novel hypothesis for the mechanism of silica particle-induced increase in cytokine production. We studied the role of iron in lipid peroxidation-dependent transcription of cytokines in macrophages by ground natural silica particles at low sublethal doses. Particle size, size distribution, surface area, and structure were determined using electron microscopy, nitrogen adsorption, and X-ray diffraction. Iron impurity concentrations before and after acid treatment were determined by energy-dispersive X-ray and inductively coupled plasma mass spectroscopy. At a low noncytotoxic dose (1 μg/ml) of 2-μm silica, the presence of iron significantly increased superoxide (O(2)(•-)), lipid peroxidation, lipid raft disruption, and cytokine production in macrophages. The iron chelators deferoxamine mesylate and diethylenetriaminepentaacetic acid were found to abrogate O(2)(•-) production and inhibit lipid peroxidation, raft disruption, and cytokine induction. Tricyclodecan-9-yl xanthate, a competitive inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), which is an upstream participant in NF-κB activation, and manganese(III) tetrakis(N-ethylpyridinium-2-yl) porphyrin, a superoxide dismutase and catalase mimic, blocked silica-stimulated cytokine production. We propose a pathway of iron-induced lipid peroxidation disrupting lipid rafts and signaling for the production of cytokines through PC-PLC in silica-exposed macrophages.
authors: School of Engineering, University of California at Merced, Merced, CA 95343, USA.
authors: Gayatri
authors: G
authors: Premasekharan
authors: Kennedy
authors: K
authors: Nguyen
authors: Janette
authors: J
authors: Contreras
authors: Virginia
authors: V
authors: Ramon
authors: Valerie Jean
authors: VJ
authors: Leppert
authors: Henry Jay
authors: HJ
authors: Forman
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002374:Catalase / Q000737:chemistry; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D019786:Gadolinium DTPA / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D021962:Membrane Microdomains / Q000187:drug effects* / Q000648:ultrastructure; D008665:Metalloporphyrins / Q000737:chemistry / Q000494:pharmacology; D008854:Microscopy, Electron; D009636:Norbornanes; D012822:Silicon Dioxide / Q000494:pharmacology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D001952:Bridged-Ring Compounds; D002614:Chelating Agents; D016207:Cytokines; D008665:Metalloporphyrins; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D012822:Silicon Dioxide; D007501:Iron; D002374:Catalase; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D003676:Deferoxamine; D019786:Gadolinium DTPA