Interleukin-6 regulates iron-related proteins through c-Jun N-terminal kinase activation in BV2 microglial cell lines.

Shida Zhou,Xinxing Du,Jun Wang,Junxia Xie,Cristoforo Scavone

doi:10.1371/journal.pone.0180464

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and subsequent DA depletion in the striatum. Microglia activation and nigral iron accumulation play important roles in the pathogenesis of PD. Activated microglia show increased iron deposits. However, the relationship between microglia activation and iron accumulation remains unclear. In the present study, we aimed to determine how iron levels affect interleukin-6 (IL-6) synthesis, and the effect of IL-6 on cellular iron metabolism in BV2 microglial cells.IL-6 mRNA was up-regulated after FAC treatment for 12 h in BV2 cells. Iron regulatory protein 1 (IRP1) and divalent metal transporter 1 (DMT1) were up-regulated and iron exporter ferroportin 1 (FPN1) was down-regulated in BV2 cells after 24 h of IL-6 treatment. Phosphorylated JNK increased significantly compared to the control after BV2 cells were treated with IL-6 for 1 h. Pretreatment with SP600125 attenuated the up-regulation of IRP1 and DMT1 and down-regulation of FPN1 (compared to IL-6-treated group). These results suggest that iron load could increase IL-6 mRNA expression in BV2 cells. Further, IL-6 likely up-regulates IRP1 and DMT1 expression and down-regulates FPN1 expression in BV2 microglial cells through JNK signaling pathways.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and subsequent dopamine (DA) depletion in the striatum
To determine whether the levels of iron transporters were responsive to interleukin 6 (IL-6) treatment in microglia, we investigated the expressions of Iron regulatory protein 1 (IRP1), divalent metal transporter1 (DMT1), and ferroportin 1 (FPN1) in BV2 cells treated for 24 h with 30 ng/ml IL-6
IRP1 and DMT1 expression increased, and FPN1 expression decreased in the IL-6-treated BV2 cells (Fig 2)

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and subsequent dopamine (DA) depletion in the striatum. Microglia activation has been observed in patients with PD. Reactive microglia become neurotoxic through the secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6)[1,2,3]. IL-1β, IL-6, and TNF-α levels increase in the brain of patients with PD [4]. Extensive studies have demonstrated that iron plays a key role in the pathogenesis of PD.

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