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Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages

Gene Therapy volume 17, pages 662–671 (2010)Cite this article

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Abstract

Neuroinflammation, as defined by activation of local glial cells and production of various inflammatory mediators, is an important feature of many neurological disorders. Expression of pro-inflammatory mediators produced by glial cells in the central nervous system (CNS) is considered to contribute to the neuropathology observed in those diseases. To diminish the production or action of pro-inflammatory mediators, we have used lentiviral (LV) vector-mediated encoding rat interleukin-10 (rIL-10) or rat interleukin-1 receptor antagonist (rIL-1ra) to direct the local, long-term expression of these anti-inflammatory cytokines in the CNS. We have shown that cultured macrophages or astroglia transduced with LV-rIL-10 or LV-rIL-1ra produced far less tumor necrosis factor (TNF)α or IL-6, respectively in response to pro-inflammatory stimuli. Moreover, intracerebroventricular (i.c.v.) administration of LV-rIL-10 or LV-rIL-1ra resulted in transduction of glial cells and macrophages and, subsequently reduced TNFα, IL-6 and inducible nitric oxide synthase (iNOS) expression in various brain regions induced by inflammatory stimuli, whereas peripheral expression of these mediators remained unaffected. In addition, expression levels of the anti-inflammatory cytokines IL-4 and transforming growth factor-β were not altered in either brain or pituitary gland. Furthermore, i.c.v. administration of LV-rIL-10 or LV-rIL-1ra given during the remission phase of chronic-relapsing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, improved the clinical outcome of the relapse phase. Thus, local application of LV vectors expressing anti-inflammatory cytokines could be of therapeutic interest to counteract pro-inflammatory processes in the brain without interfering with the peripheral production of inflammatory mediators.

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Acknowledgements

We thank Prof Dr Fred Tilders for his interest and valuable discussions. This work was financially supported by the European Community (Cybrainet program) and a VU-breedtestrategie grant (Vrije Universiteit, Amsterdam, The Netherlands).

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  1. D Mercier

    Present address: 5Current address: Qiagen S.A., Courtaboeuf Cedex, France.,

  2. M E van Strien and D Mercier: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    M E van Strien, D Mercier, B Drukarch, J J P Brevé, R Binnekade, J G J M Bol & A-M van Dam

  2. Department of Endocrinology, National Institute for Biochemical Standards and Control (NIBSC), Potters Bar, UK

    S Poole

  3. Department of Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    B Blits & J Verhaagen

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van Strien, M., Mercier, D., Drukarch, B. et al. Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages. Gene Ther 17, 662–671 (2010). https://doi.org/10.1038/gt.2010.8

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