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The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes

Gene Therapy volume 9, pages 1120–1126 (2002)Cite this article

Abstract

Recent studies have demonstrated that intravenous administration of a plasmid DNA–cationic liposome complex (lipoplex) induced significant proinflammatory cytokine production in blood and inhibited transgene expression in pulmonary endothelial cells. In this study, we examined the effects of gadolinium chloride (GdCl3) pretreatment on the biodistribution and induction of proinflammatory cytokine production and transgene expression after intravenous injection of a lipoplex in mice. GdCl3 is known to transiently deplete liver Kupffer cells and spleen macrophages after intravenous administration. Intravenous administration of a lipoplex triggers high levels of proinflammatory cytokine production, such as TNF-α, IFN-γ and IL-12 in serum and a large amount of 32P-labeled lipoplex accumulates in the liver 1 h after intravenous administration. However, pretreatment with GdCl3 dramatically reduces serum levels of these cytokines and liver accumulation of the lipoplex. RT-PCR analysis showed that mRNA expression of TNF-α greatly increases in the liver and spleen after lipoplex injection and that pretreatment with GdCl3 reduces mRNA expression in these organs. Messenger RNA expression of TNF-α in the liver occurs in non-parenchymal cells (sinusoidal endothelial cells and/or Kupffer cells). Inhibition of cytokine production by pretreatment with GdCl3 leads to recovery of transgene expression in the lung following the second injection of lipoplex, which was reduced following the first injection of lipoplex. Thus, the present study demonstrates that tissue macrophages involving liver Kupffer cells and spleen macrophages are closely involved in TNF-α production following i.v. administration of the lipoplex. It is also suggested that avoiding lipoplex uptake and subsequent cytokine production by these cells would be a useful method of maintaining a high level of gene expression in the lung after repeated injections.

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Acknowledgements

This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.

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Author notes

  1. F Sakurai

    Present address: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

Authors and Affiliations

  1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    F Sakurai, T Terada, F Yamashita & M Hashida

  2. Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    K Yasuda & Y Takakura

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Sakurai, F., Terada, T., Yasuda, K. et al. The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes. Gene Ther 9, 1120–1126 (2002). https://doi.org/10.1038/sj.gt.3301784

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  • DOI: https://doi.org/10.1038/sj.gt.3301784

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