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The Role of Tissue Macrophages in the Induction of Proinflammatory

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The Role of Tissue Macrophages in the Induction of Proinflammatory Gene Therapy (2002) 9, 1120–1126 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00 www.nature.com/gt BRIEF COMMUNICATION The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes F Sakurai1,3, T Terada1, K Yasuda2, F Yamashita1, Y Takakura2 and M Hashida1 1Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and 2Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Recent studies have demonstrated that intravenous admin- increases in the liver and spleen after lipoplex injection and istration of a plasmid DNA–cationic liposome complex that pretreatment with GdCl3 reduces mRNA expression in (lipoplex) induced significant proinflammatory cytokine pro- these organs. Messenger RNA expression of TNF-␣ in the duction in blood and inhibited transgene expression in pul- liver occurs in non-parenchymal cells (sinusoidal endothelial monary endothelial cells. In this study, we examined the cells and/or Kupffer cells). Inhibition of cytokine production effects of gadolinium chloride (GdCl3) pretreatment on the by pretreatment with GdCl3 leads to recovery of transgene biodistribution and induction of proinflammatory cytokine expression in the lung following the second injection of lipo- production and transgene expression after intravenous injec- plex, which was reduced following the first injection of lipo- tion of a lipoplex in mice. GdCl3 is known to transiently plex. Thus, the present study demonstrates that tissue deplete liver Kupffer cells and spleen macrophages after macrophages involving liver Kupffer cells and spleen macro- intravenous administration. Intravenous administration of a phages are closely involved in TNF-␣ production following lipoplex triggers high levels of proinflammatory cytokine pro- i.v. administration of the lipoplex. It is also suggested that duction, such as TNF-␣, IFN-␥ and IL-12 in serum and a avoiding lipoplex uptake and subsequent cytokine pro- large amount of 32P-labeled lipoplex accumulates in the liver duction by these cells would be a useful method of main- 1 h after intravenous administration. However, pretreatment taining a high level of gene expression in the lung after with GdCl3 dramatically reduces serum levels of these cyto- repeated injections. kines and liver accumulation of the lipoplex. RT-PCR analy- Gene Therapy (2002) 9, 1120–1126. doi:10.1038/sj.gt.3301784 sis showed that mRNA expression of TNF-␣ greatly ␣ Keywords: TNF- ; lipoplex; liver Kupffer cells; spleen macrophage; GdCl3; plasmid DNA; proinflammatory cytokines Several recent studies have shown that intravenous to induce production of large quantities of proinflamma- administration of plasmid DNA–cationic liposome com- tory cytokines, such as TNF-␣, IFN-␥, and IL-12.6–8 It plexes (ie lipoplexes) leads to systemic gene expression, appears that such cytokines activate the immune system particularly in the lung.1–3 Therefore, increasing attention and induce strong antitumor effects in mice.4,5 On the has focused on the development of efficient in vivo gene other hand, Li et al have shown that such cytokines, delivery systems. However, intravenous administration which are secreted after intravenous injection of lipo- of cationic lipid vectors containing plasmid DNA has plexes, can be toxic and cause short-term gene expression been shown to initiate potent cytokine responses.4,5 High and refractory behavior on repeated dosing at frequent amounts of proinflammatory cytokines are produced in intervals.9,10 This is a potential problem in gene therapy blood after lipoplex injection since bacterially derived using plasmid DNA. However, it is not known which plasmid DNA is recognized as foreign material by ver- cells are responsible for the induction of cytokine tebrate cells. Unmethylated CpG sequences in plasmid production after lipoplex administration. DNA, occurring at a higher frequency in bacterial DNA, The liver and spleen are well known to play a central have been reported to have strong stimulatory effects on role in the removal of foreign particles and invasive lymphocytes, NK cells, dendritic cells and macrophages microorganisms from the circulation, mainly via Kupffer cells and spleen macrophages.11,12 Kupffer cells are large liver macrophages and their functions are activated by a Correspondence: M Hashida, Department of Drug Delivery Research, variety of particles, viruses, lipopolysaccharides and Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, TNF-␣.13 The phagocytosis of parasites by Kupffer cells Kyoto 606-8501, Japan is accompanied by the release of TNF-␣. Spleen macro- 3Present Address: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, phages are also activated in addition to liver Kupffer Tokyo 158-8501, Japan cells. We and other groups have also reported that lipo- Received 28 November 2001; accepted 9 April 2002 plexes accumulate in the liver and spleen, as well as the Proinflammatory cytokine production by lipoplex F Sakurai et al 1121 lung after intravenous administration and liver Kupffer point). A lower recovery of radioactivity in the GdCl3- cells and spleen macrophages are directly involved in the pretreated mice would be due to distribution to other uptake of lipoplexes.14–17 These data suggest that these organs and excretion into the urine, which we did not cells may play an important role in the production of pro- measure in the present study. The radioactivity would inflammatory cytokines. These cells are also involved in be derived from degradation products of 32P-DNA. We the uptake of adenovirus and cytokine production after speculated that faster DNA degradation would occur in intravenous administration of recombinant adenovirus the GdCl3-pretreated mice compared with control ani- vectors.11,18,19 In this study, we evaluated the effects of mals. After intravenous injection of lipoplex, plasmid pretreatment with GdCl3 on the production of proin- DNA would be dissociated from the cationic liposomes flammatory cytokines and gene expression in the lung in the blood circulation by the interaction with biological after lipoplex injection. Several studies have reported that components, such as blood constituents and proteogly- 25,27,28 intravenous injection of GdCl3, a rare earth metal salt, is cans. Free DNA dissociated from cationic liposomes able to not only block the phagocytosis of macrophages is susceptible to degradation by nucleases in the blood in liver and spleen, but also eliminate them and that a and the degradation products are excreted into the urine single injection of GdCl3 blocks phagocytosis in more via the kidney and distributed throughout the body. 20,21 29 than 90% of Kupffer cells. GdCl3 has also been used Kawabata et al have demonstrated these processes after to evaluate the function of these cells in many reports.22,23 i.v. injection of naked plasmid DNA labeled with 32P. We report here that liver Kupffer cells and spleen macro- Lipoplex would be more susceptible to the interaction phages play an important role in the induction of proin- with these components in the GdCl3-pretreated mice due flammatory cytokine production after intravenous to decreased lipolex uptake by the macrophages. In fact, administration of a lipoplex and that prevention of lipo- the radioactivity in the kidney and heart of GdCl3-pre- plex uptake by these cells eliminates the refractory treated mice was slightly higher than that of saline-pre- behavior to repeated injection. treated mice (data not shown). On the other hand, the It is necessary for immune cells to endocytose DNA- release of 32P-DNA degradation products from the cells containing CpG motifs in order to produce cytokines by after endocytosis followed by lysosomal degradation will CpG motif-mediated induction.6,24 Therefore, we first not significantly affect the biodistribution results in this examined the biodistribution of a 32P-lipoplex after intra- study. Enzymatic degradation most probably occurs in venous administration in saline-pretreated and GdCl3- the bloodstream. Even following intravenous injection of pretreated mice. Mice received intravenous injections of naked 32P-DNA, the level of the radioactivity in the liver a GdCl3 solution or saline 24 h before lipoplex adminis- derived from DNA taken up by liver non-parenchymal tration. The lipoplex was rapidly removed from the cells was almost constant for 30 min.29 In the case of lipo- bloodstream and only a few percent of the lipoplex plex, intracellular stability of DNA should be enhanced. remained in the blood 10 min after injection in both In addition, more than 20 min elapsed after injection groups (data not shown). Rapid lung accumulation of the before endocytosis of the lipoplex into the lung endo- lipoplex was observed in both groups immediately after thelial cells took place.14,30 Wattiaux et al31 have also i.v. administration, as reported by other groups (Figure examined the subcellular distribution of radiolabeled 1a).25,26 The lung accumulation of the lipoplex gradually DNA complexed with cationic lipids in rat liver and sug- decreased in both groups, however, a significantly higher gested that DNA complexed with cationic lipid reached amount of lipoplex was left in the lung of GdCl3-pre- the lysosomal compartment more than 1 h later after treated mice compared with saline-pretreated
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