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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA
Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, North Carolina (L.Q., P.M.F.); Neuropharmacology Section, Laboratory of Pharmacology and Chemistry (L.Q., M.L.B., C.-f.L., H.P., B.W., J.-S.H.), The National Center for Toxicogenomics (S.-J.W.), and Confocal Microscopy Center, Laboratory of Signal Transduction (J.R.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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-
, 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.
Address correspondence to: Dr. Patrick M. Flood, The Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455. E-mail: pat_flood{at}dentistry.unc.edu
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