Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase.
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.
Qian
Li
L
The Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455, USA.
Block
Michelle L
ML
Wei
Sung-Jen
SJ
Lin
Chiou-Feng
CF
Reece
Jeffrey
J
Pang
Hao
H
Wilson
Belinda
B
Hong
Jau-Shyong
JS
Flood
Patrick M
PM
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
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