BV-2 stimulation by lactacystin results in a strong inflammatory reaction and apoptotic neuronal death in SH-SY5Y cells.
Neuroinflammation plays a role in the pathomechanism of many neurodegenerative diseases, including Parkinson disease (PD). Proteasome inhibition has also been known to be involved in the pathology of PD. Recent studies have reported that microglial activation and dopaminergic cell death were observed in in vivo lactacystin-induced models of PD. In the present study, we investigated whether proteasome inhibition had a direct effect on the inflammatory reaction. Lactacystin treatment increased the amount of nitric oxide and tumor necrosis factor alpha (TNF-alpha) in culture media containing murine microglia (BV-2). Neuronal cell death was more pronounced when the culture media containing BV-2 cells (BV-2 conditioned media; BV-2 CM) were harvested and treated with human dopaminergic neurons (SH-SY5Y) than when treated with lactacystin alone. Apoptosis was markedly increased by treatment with BV-2 CM, which could be mitigated by pretreatment with minocycline and N(omega)-nitro-l-arginine methyl ester (L-NAME). These results suggest that proteasome inhibition can directly trigger neuroinflammation, which leads to neuronal death.
Kwon
Seon-Joo
SJ
Department of Neurology, Seoul National University College of Medicine, Republic of Korea.
Ahn
Tae-Beom
TB
Yoon
Min-Yung
MY
Jeon
Beom S
BS
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D046988:Proteasome Endopeptidase Complex / Q000235:genetics
D000900:Anti-Bacterial Agents; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D046988:Proteasome Endopeptidase Complex; D008911:Minocycline; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine