title: Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase.
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-alpha, 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 p47(phox) 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.
authors.affiliation: The Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
authors.forename: Sung-Jen
authors.initials: SJ
authors.lastname: Wei
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Reece
authors.forename: Hao
authors.initials: H
authors.lastname: Pang
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Flood
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000494:pharmacology*; D053613:Janus Kinase 1; D008070:Lipopolysaccharides / Q000633:toxicity*; D008636:Mesencephalon / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D016753:Interleukin-10; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; D053613:Janus Kinase 1