Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Xie, Junxia¹ 

[1] Qingdao Univ, Coll Med, Dept Physiol, Shandong Prov Key Lab Pathogenesis & Prevent Neur, Qingdao 266071, Peoples R China

关键词: Interleukin-1 beta;    Tumor necrosis factor-alpha;    Iron;    Iron regulatory protein 1;    Microglia;    Neuron;   

DOI  :  10.1016/j.bbadis.2013.01.021

来源: Elsevier

【 摘 要 】

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 interleuldn-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) released by microglia, could affect cellular iron transportation in primary cultured ventral mesencephalic (VM) neurons. The results showed that IL-1 beta or TNF-alpha 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-1 beta or TNF-alpha treated VM neurons. IRP1 upregulation could be fully abolished by co-administration of radical scavenger N-acetyl-L-cysteine and inducible NO synthetase inhibitor N-omega-nitro-L-arginine methyl ester hydrochloride. Further experiments demonstrated that IL-1 beta and TNF-alpha 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-1 beta and TNF-alpha 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. (C) 2013 Elsevier B.V. All rights reserved.

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