Abstract
To find out whether the Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in the expression of hepcidin in the mouse brain in vivo, we investigated the phosphorylation of STAT3, as well as the expression of hepcidin mRNA, ferroportin 1 (Fpn1) and ferritin light chain (Ft-L) proteins in the cortex and hippocampus of LPS-treated wild type (IL-6+/+) and IL-6 knockout (IL-6-/-) mice. We demonstrated that IL-6 knockout could significantly reduce the response of hepcidin mRNA, phospho-STAT3, Fpn1 and Ft-L protein expression to LPS treatment, in both the cortex and hippocampus of mice. Also, Stattic, an inhibitor of STAT3, significantly reduced the expression of phospho-STAT3 and hepcidin mRNA in the cortex and hippocampus of the LPS-treated wild type mice. These findings provide in vivo evidence for the involvement of the IL-6/STAT3 signaling pathway in the expression of hepcidin.
Highlights
Iron is the most abundant trace metal in the brain (Beard et al, 1993)
To confirm the role of IL-6 in hepcidin expression’s response to LPS treatment, we investigated the effects of LPS treatment on the expression of hepcidin mRNA in IL-6 knockout (IL-6−/−) mice and wild type (IL-6+/+) mice
RT-PCR analysis showed that there were no significant differences in the expression of hepcidin mRNA in the cortex (Figure 2A) and hippocampus (Figure 2B) between the IL-6+/+ and the IL-6−/− mice, both treated with phosphate buffered saline (PBS)
Summary
Iron is the most abundant trace metal in the brain (Beard et al, 1993). The importance of iron for normal neurological function has been well-established. High iron and iron-induced oxidative stress in the brain has been demonstrated to be an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia (Ke and Qian, 2003; Rouault, 2013; Arber et al, 2016), and has been proposed to play a causative role in at least some of the other neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease (Qian and Shen, 2001; Peters et al, 2015; Belaidi and Bush, 2016; Hare and Double, 2016). It has been proposed that the disrupted expression or function of proteins involved in brain iron metabolism may be one of initial causes of abnormal iron accumulation
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