Abstract
The role of anti-inflammatory cytokines in Parkinson's disease is not completely understood. In this study, using mesencephalic neuron-glia cultures, we report that both pretreatment and post-treatment of rat mesencephalic neuron-glia cultures with interleukin (IL)-10, a natural immune modulator, reduced lipopolysaccharide (LPS)-induced DA neurotoxicity. The main purpose of this study was to elucidate the molecular mechanism underlying IL-10-elicited neuroprotection. IL-10 significantly inhibited LPS-induced production of tumor necrosis factor-α, nitric oxide, and extracellular superoxide in microglia cells. In addition, using reconstituted neuron and glia cell cultures, IL-10 was shown to be neuroprotective only in the presence of microglia. More importantly, IL-10 failed to protect DA neurons in cultures from mice lacking NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells, suggesting the critical role of PHOX in IL-10 neuroprotection. This conclusion was further supported by the finding that IL-10 inhibited LPS-induced translocation of the cytosolic subunit of NADPH oxidase p47phox to the membrane. When the Janus tyrosine kinase (JAK) 1 signaling pathway was blocked, IL-10 failed to attenuate LPS-induced superoxide production, indicating that the JAK1 signaling cascade mediates the inhibitory effect of IL-10. Together, our results suggest that IL-10 inhibits LPS-induced DA neurotoxicity through the inhibition of PHOX activity in a JAK1-dependent mechanism.
Footnotes
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This work was supported by National Institutes of Health Grant DE-13079 from the National Institute for Dental and Craniofacial Research and was also supported in part by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences.
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Preliminary data were presented at the 16th Congress of Parkinson's Disease Meeting; 2005 Jun 5-9; Berlin, Germany. World Federation of Neurology, London, UK.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106351.
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ABBREVIATIONS: PD, Parkinson's disease; DA, dopaminergic; NO, nitric oxide; PHOX, NADPH oxidase; LPS, lipopolysaccharide; TNF, tumor necrosis factor; IL, interleukin; CNS, central nervous system; JAK, Janus tyrosine kinase; OX-42, CR3 complement receptor; DCFH-DA, dichlorodihydrofluorescein diacetate; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; TH-IR, tyrosine hydroxylase-immunoreactive; PG, prostaglandin; SOD, superoxide dismutase; WST, water-soluble tetrazolium salt; HBSS, Hanks' balanced salt solution; ROS, reactive oxygen species; PCR, polymerase chain reaction; iNOS, inducible nitric-oxide synthase; COX, cyclooxygenase; STAT, signal transducer and activator of transcription; NF, nuclear factor; HAPI, highly aggressively proliferating immortalized.
- Received April 17, 2006.
- Accepted June 27, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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