title: Protection against TNFα-dependent liver toxicity by intraperitoneal liposome delivered DsiRNA targeting TNFα in vivo.
abstract: Tumor necrosis factor-alpha (TNFα) is a classic proinflammatory cytokine implicated in the pathogenesis of several autoimmune and inflammatory diseases including viral encephalitis. Macrophages being major producers of TNFα are thus attractive targets for in vivo RNA interference (RNAi) mediated down regulation of TNFα. The application of RNAi technology to in vivo models however presents obstacles, including rapid degradation of RNA duplexes in plasma, insufficient delivery to the target cell population and toxicity associated with intravenous administration of synthetic RNAs and carrier compounds. We exploited the phagocytic ability of macrophages for delivery of Dicer-substrate small interfering RNAs (DsiRNAs) targeting TNFα (DsiTNFα) by intraperitoneal administration of lipid-DsiRNA complexes that were efficiently taken up by peritoneal macrophages and other phagocytic cells. We report that DsiTNFα-lipid complexes delivered intraperitoneally altered the disease outcome in an acute sepsis model. Down-regulation of TNFα in peritoneal CD11b+ monocytes reduced liver damage in C57BL/6 mice and significantly delayed acute mortality in mice treated with low dose LPS plus d-galactosamine (D-GalN).
authors.affiliation: Division of Immunology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Patric
authors.initials: P
authors.lastname: Lundberg
authors.forename: Hui-Jung
authors.initials: HJ
authors.lastname: Yang
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Jung
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.forename: Scott D
authors.initials: SD
authors.lastname: Rose
authors.forename: Edouard M
authors.initials: EM
authors.lastname: Cantin
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D005688:Galactosamine / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D043244:Ribonuclease III / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000150:complications / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D039481:CD11b Antigen; D008070:Lipopolysaccharides; D008081:Liposomes; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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