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HSV-mediated transfer of interleukin-10 reduces inflammatory pain through modulation of membrane tumor necrosis factor α in spinal cord microglia

Gene Therapy volume 15, pages 183–190 (2008)Cite this article

Abstract

To dissect the molecular basis of the neuroimmune response associated with the genesis of inflammatory (nociceptive) pain, we constructed a herpes simplex virus-based gene transfer vector to express the antiinflammatory cytokine interleukin-10 (IL-10), and used it to examine the effect of IL-10 expression in activated microglial cells in vitro, and in inflammatory pain in vivo. IL-10 reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and decreased the expression of full-length membrane spanning tumor necrosis factor-α (mTNFα) following lipopolysaccharide stimulation of microglia in vitro. IL-10 also reduced intracellular cleavage of mTNFα and release of the soluble cleavage product sTNFα. Similar effects on TNFα expression were observed when the cells were pretreated with a p38 MAPK inhibitor. In animals, injection of a dilute solution of formalin in the skin resulted in an increase in mTNFα in spinal dorsal horn, without detectable sTNFα. Local release of IL-10 achieved by gene transfer reduced the number of spontaneous flinches in the early and delayed phases of the formalin test of inflammatory pain. The effect of IL-10 on nocisponsive behavior correlated with a block in phosphorylation of p38 and reduced expression of 26 kDa mTNFα in spinal microglia. The results emphasize the key role played by membrane TNFα in the spinal neuroimmune response in pain caused by peripheral inflammation.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (DJF and MM) and the Department of Veterans Affairs (DJF and MM). We thank Dr Joseph Glorioso (University of Pittsburgh) for providing the HSV vector backbone and 7b cells, Dr JR Connor (Pennsylvania State University College of Medicine) for the HAPI cells, Molly Rockstad for technical assistance, Vikram Thakur Singh for propagation of the vectors and Shue Liu for tissue culture.

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Authors and Affiliations

  1. Department of Neurology, University of Michigan Medical School and GRECC and Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA

    Z Zhou, X Peng, S Hao, D J Fink & M Mata

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  1. Z Zhou
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  2. X Peng
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  3. S Hao
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  4. D J Fink
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Correspondence to M Mata.

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Zhou, Z., Peng, X., Hao, S. et al. HSV-mediated transfer of interleukin-10 reduces inflammatory pain through modulation of membrane tumor necrosis factor α in spinal cord microglia. Gene Ther 15, 183–190 (2008). https://doi.org/10.1038/sj.gt.3303054

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