| Comparison of the type of liposome involving cytokine production induced by non-CpG Lipoplex in macrophages. | |
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MedLine Citation:
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PMID: 20047296 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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To improve the transfection efficiency of plasmid DNA (pDNA) into cells, various types of cationic liposome have been used to prepare pDNA/cationic liposome complexes (lipoplexes). It is well-known that lipoplexes induce a large amount of proinflammatory cytokines because unmethylated CpG dinucleotides (CpG motifs) abundantly present in pDNA are recognized by Toll-like receptor-9 (TLR9) expressed in immune cells such as macrophages and dendritic cells. This nonspecific cytokine production is problematic in nonviral gene therapy. Moreover, recent studies have demonstrated that lipoplexes induce not only proinflammatory cytokines but also another type of cytokine, type I interferons (IFNs), irrespective of the frequency of CpG motifs in DNA and the expression of TLR9. To gain more insight into the CpG motif- and TLR9-independent induction of type I IFNs and proinflammatory cytokines by lipoplex, macrophage activation was evaluated in vitro using various cationic liposomes complexed with pDNA containing no CpG motifs. The production of IFN-beta, TNF-alpha and IL-6 by lipoplex was confirmed to be induced independently of the interaction between CpG DNA and TLR9 in macrophages from TLR9-knockout mice. Then, the release of the cytokines, the mRNA expression of Z-DNA binding protein-1 (Zbp1), a cytosolic double-stranded DNA sensor, and the cellular uptake of pDNA were examined in a macrophage-like cell line, RAW264.7. The level of cytokine production and the increase in the Zbp1 mRNA varied depending on the type of cationic liposome used. A good correlation was observed between the cytokine level and the Zbp1 mRNA. A confocal microscopic study using fluorescently labeled pDNA complexes showed that the complexes that released a lot of cytokines showed an enhanced distribution of pDNA-derived fluorescence into the cytosol. These results suggest that different intracellular trafficking derived from the type of liposomes determines the recognition of pDNA by ZBP1 after uptake of lipoplexes by the macrophages, followed by the release of type I IFNs and inflammatory cytokines. The present study demonstrates that cationic liposomes should be selected based on these findings for optimization of DNA-based therapies using lipoplexes. |
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Authors:
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Sachiyo Yasuda; Hiroyuki Yoshida; Makiya Nishikawa; Yoshinobu Takakura |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular pharmaceutics Volume: 7 ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-05 Completed Date: 2010-06-29 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: United States |
Other Details:
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Languages: eng Pagination: 533-42 Citation Subset: IM |
Affiliation:
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Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cytokines / biosynthesis* DNA / genetics Glycoproteins / genetics Interferon-beta / metabolism Interleukin-6 / metabolism Liposomes / chemistry*, metabolism*, pharmacology* Macrophages / drug effects*, metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Models, Theoretical Plasmids / genetics Toll-Like Receptor 9 / genetics Tumor Necrosis Factor-alpha / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Glycoproteins; 0/Interleukin-6; 0/Liposomes; 0/Toll-Like Receptor 9; 0/Tumor Necrosis Factor-alpha; 0/Zbp1 protein, mouse; 77238-31-4/Interferon-beta; 9007-49-2/DNA |
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