title: Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons.
abstract: Both inflammatory processes associated with microglia activation and abnormal iron deposit in dopaminergic neurons are involved in the pathogenesis of Parkinson's disease (PD). However, the relationship between neuroinflammation and iron accumulation was not fully elucidated. In the present study, we aimed to investigate whether the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) released by microglia, could affect cellular iron transportation in primary cultured ventral mesencephalic (VM) neurons. The results showed that IL-1β or TNF-α treatment led to increased ferrous iron influx and decreased iron efflux in these cells, due to the upregulation of divalent metal transporter 1 with the iron response element (DMT1+IRE) and downregulation of ferroportin1 (FPN1). Increased levels of iron regulatory protein 1 (IRP1), transferrin receptor 1 (TfR1) and hepcidin were also observed in IL-1β or TNF-α treated VM neurons. IRP1 upregulation could be fully abolished by co-administration of radical scavenger N-acetyl-l-cysteine and inducible NO synthetase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride. Further experiments demonstrated that IL-1β and TNF-α release was remarkably enhanced by iron load in activated microglia triggered by lipopolysaccharide or 1-methyl-4-phenylpyridinium (MPP(+)). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice, salicylate application could not block DMT1+IRE upregulation in dopaminergic neurons of substantia nigra. These results suggested that IL-1β and TNF-α released by microglia, especially under the condition of iron load, might contribute to iron accumulation in VM neurons by upregulating IRP1 and hepcidin levels through reactive oxygen/nitrogen species production. This might provide a new insight into unraveling that microglia might aggravate this iron mediated neuropathologies in PD.
authors: Department of Physiology, Medical College of Qingdao University, Qingdao, China.
authors: Jia
authors: J
authors: Wang
authors: Ning
authors: N
authors: Song
authors: Hong
authors: H
authors: Jiang
authors: Jun
authors: J
authors: Wang
authors: Junxia
authors: J
authors: Xie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D064451:Hepcidins; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D053583:Interleukin-1beta; D007501:Iron; D035941:Iron Regulatory Protein 1; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012459:Salicylates; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D000099236:Solute Carrier Family 11, Member 2; C579599:Hamp protein, mouse; C578703:Hamp protein, rat