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Activation of microglia by human neuromelanin is NF‐κB‐dependent and involves p38 mitogen‐activated protein kinase: implications for Parkinson's disease
Author(s) -
Wilms Henrik,
Rosenstiel Philip,
Sievers Jobst,
Deuschl Günther,
Zecca Luigi,
Lucius Ralph
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0314fje
Subject(s) - neuromelanin , microglia , p38 mitogen activated protein kinases , proinflammatory cytokine , protein kinase a , kinase , tumor necrosis factor alpha , neuroinflammation , mapk/erk pathway , microbiology and biotechnology , signal transduction , nf κb , inflammation , biology , cancer research , immunology , neuroscience , dopaminergic , dopamine , substantia nigra
It has been suggested that microglial inflammation augments the progression of Parkinson's disease (PD). However, endogenous factors initiating microglial activation are largely unknown. We therefore investigated the effects of human neuromelanin (NM) on the release of neurotoxic mediators and the underlying signaling pathways from rat microglia in vitro. The addition of NM to microglial cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor κB (NF‐κB) via phosphorylation and degradation of the inhibitor protein κB (IκB), and led to an up‐regulation of tumor necrosis factor α, interleukin‐6, and nitric oxide. The impairment of NF‐κB function by the IκB kinase inhibitor sulfasalazine was paralleled by a decline in neurotoxic mediators. NM also activated p38 mitogen‐activated protein kinase (MAPK), the inhibition of this pathway by SB203580 diminished phosphorylation of the transactivation domain of the p65 subunit of NF‐κB. These findings demonstrate a crucial role of NM in the pathogenesis of PD by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin, and chronification of inflammation. The antagonization of microglial activation by a pharmacological intervention targeting microglial NF‐κB or p38 MAPK could point to additional venues in the treatment of PD.