Neurochemical Research

, Volume 43, Issue 8, pp 1624–1630 | Cite as

Different Characteristics of Hepcidin Expression in IL-6+/+ and IL-6−/− Neurons and Astrocytes Treated with Lipopolysaccharides

  • Juan Ma
  • Fa-Li Zhang
  • Gan ZhouEmail author
  • Yu-Xin BaoEmail author
  • Yuan Shen
  • Zhong-Ming QianEmail author
Original Paper


A region-specific regulation of inflammation on the expression hepcidin in the brain has been demonstrated, however, it remains unknown whether there is also a cell-specific regulation of inflammation on hepcidin in the brain. Here, we investigated the effects of lipopolysaccharides (LPS) on the expression of hepcidin mRNA and also the expression of IL-6 mRNA, the phosphorylation of STAT3 and the expression of ferroportin 1 (Fpn1) and ferritin light chain (Ft-L) proteins in neurons and astrocytes obtained from wild type (IL-6+/+) and IL-6 knockout (IL-6−/−) mice. We demonstrated that the responses of the expression of hepcidin and IL-6 mRNAs, the phosphorylation of STAT3, and the expression of Fpn1 protein to LPS in IL-6+/+ astrocytes and also the responses of the expression of hepcidin mRNA, the phosphorylation of STAT3 and the expression of Fpn1 protein to IL-6 in IL-6−/− astrocytes were much stronger than those in IL-6+/+ and IL-6−/− neurons. A significant increase in Ft-L was found in LPS-treated IL-6+/+ and IL-6-treated IL-6−/− astrocytes, but not in LPS-treated IL-6+/+ and IL-6-treated IL-6−/− neurons. Our findings provide in vitro evidence for the existence of a cell-specific regulation of LPS on the expression of hepcidin and also Ft-L in the brain.


Neuron and astrocyte Lipopolysaccharides (LPS) Hepcidin and ferroportin 1 (Fpn1) Ferritin light chain (Ft-L) and cell iron content IL-6/STAT3 pathway 





Ferroportin 1


Ferritin light chain


IL-6 knockout




Signal transducer and activator of transcription 3



The studies in our laboratories were supported by National Natural Science Foundation of China (31330035, 31571195), and the National Basic Research Program of China (973) (2014CB541604).

Author Contributions

GZ, YXB and ZMQ conceived, organized and supervised the study; JM, FLZ and YS performed the experiments; YXB and GZ contributed to the analysis of data; ZMQ prepared and wrote the manuscript. All authors read and approved the final edition of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.


  1. 1.
    Ke Y, Qian ZM (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2:246–253CrossRefPubMedGoogle Scholar
  2. 2.
    Ke Y, Qian ZM (2007) Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol 83:149–173CrossRefPubMedGoogle Scholar
  3. 3.
    Krause A, Neitz S, Magrert HJ, Schulz A, Forssmann WG, Schulz P, Knappe A (2000) LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 480:147–150CrossRefPubMedGoogle Scholar
  4. 4.
    Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276:7806–7810CrossRefPubMedGoogle Scholar
  5. 5.
    Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819CrossRefPubMedGoogle Scholar
  6. 6.
    Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98:8780–8785CrossRefPubMedGoogle Scholar
  7. 7.
    Ganz T (2006) Hepcidin—a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol 306:183–198PubMedGoogle Scholar
  8. 8.
    Zechel S, Huber-Wittmer K, von Bohlen und Halbach O (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res 4:790–800CrossRefGoogle Scholar
  9. 9.
    Wang Q, Du F, Qian Z-M, Ge XH, Zhu L, Yung WH, Yang L, Ke Y (2008) Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain. Endocrinology 149:3920–3925CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hänninen MM, Haapasalo J, Haapasalo H, Fleming RE, Britton RS, Bacon BR, Parkkila S (2009) Expression of iron-related genes in human brain and brain tumors. BMC Neurosci 10:36CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Du F, Qian ZM, Zhu L, Wu XM, Qian C, Chan R, Ke Y (2010) Purity, cell viability, expression of GFAP and bystin in astrocytes cultured by different procedures. J Cell Biochem 109:30–37PubMedGoogle Scholar
  12. 12.
    Raha-Chowdhury R, Raha AA, Forostyak S, Zhao JW, Stott SR, Bomford A (2015) Expression and cellular localization of hepcidin mRNA and protein in normal rat brain. BMC Neurosci 16:24CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lu LN, Qian ZM, Wu KC, Yung WH, Ke Y (2016) Expression of iron transporters and pathological hallmarks of Parkinson’s and Alzheimer’s diseases in the brain of young, adult, and aged rats. Mol Neurobiol 54:5213–5224CrossRefPubMedGoogle Scholar
  14. 14.
    Gong J, Du F, Qian ZM, Luo QQ, Sheng Y, Yung WH, Xu YX, Ke Y (2016) Pre-treatment of rats with ad-hepcidin prevents iron-induced oxidative stress in the brain. Free Radic Biol Med 90:126–132CrossRefPubMedGoogle Scholar
  15. 15.
    Wang SM, Fu LJ, Duan XL, Crooks DR, Yu P, Qian ZM, Di XJ, Li J, Rouault TA, Chang YZ (2010) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci 67:123–133CrossRefPubMedGoogle Scholar
  16. 16.
    Qian ZM, He X, Liang T, Wu KC, Yan YC, Lu LN, Yang G, Luo QQ, Yung WH, Ke Y (2014) Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway. Mol Neurobiol 50:811–820CrossRefPubMedGoogle Scholar
  17. 17.
    Xu YX, Du F, Jiang LR, Gong J, Zhou YF, Luo QQ, Qian ZM, Ke Y (2015) Effects of aspirin on expression of iron transport and storage proteins in BV-2 microglial cells. Neurochem Int 91:72–77CrossRefPubMedGoogle Scholar
  18. 18.
    Li WY, Li FM, Zhou YF, Wen ZM, Ma J, Ya K, Qian ZM (2016) Aspirin down regulates hepcidin by inhibiting NF-κB and IL6/JAK2/STAT3 pathways in BV-2 microglial cells treated with lipopolysaccharide. Int J Mol Sci 17:E1921CrossRefPubMedGoogle Scholar
  19. 19.
    Huang SN, Ruan HZ, Chen MY, Zhou G, Qian ZM (2018) Aspirin increases ferroportin 1 expression by inhibiting hepcidin via the JAK/STAT3 pathway in interleukin 6-treated PC-12 cells. Neurosci Lett 662:1–5CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang FL, Hou HM, Yin ZN, Chang L, Li FM, Chen YJ, Ke Y, Qian ZM (2017) Impairment of hepcidin upregulation by lipopolysaccharide in the interleukin-6 knockout mouse brain. Front Mol Neurosci 10:367CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ke Y, Ho K, Du J, Zhu L, Xu Y, Wang Q, Wang CY, Li L, Ge X, Chang Y, Qian ZM (2006) Role of soluble ceruloplasmin in iron uptake by midbrain and hippocampus neurons. J Cell Biochem 98:912–919CrossRefPubMedGoogle Scholar
  22. 22.
    Zhao ST, Huang XT, Zhang C, Ke Y (2012) Humanin protects cortical neurons from ischemia and reperfusion injury by the increased activity of superoxide dismutase. Neurochem Res 37:153–160CrossRefPubMedGoogle Scholar
  23. 23.
    Qian ZM, Liao QK, To Y, Ke Y, Tsoi YK, Wang GF, Ho KP (2000) Transferrin-bound and transferrin free iron uptake by cultured rat astrocytes. Cell Mol Biol 46:541–548PubMedGoogle Scholar
  24. 24.
    Du F, Zhu L, Qian ZM, Wu XM, Yung WH, Ke Y (2010) Hyperthermic preconditioning protects astrocytes from ischemia/reperfusion injury by up-regulation of HIF-1 alpha expression and binding activity. Biochim Biophys Acta 1802:1048–1053CrossRefPubMedGoogle Scholar
  25. 25.
    Chang YZ, Ke Y, Du J, Halpern GM, Ho KP, Zhu L, Gu X, Xu YJ, Wang Q, Li LZ, Wang CY, Qian ZM (2006) Increased divalent metal transporter 1 expression might be associated with the neurotoxicity of L-DOPA. Mol Pharmacol 69:968–974PubMedGoogle Scholar
  26. 26.
    Huang XT, Qian ZM, He X, Gong Q, Wu KC, Jiang LR, Lu LN, Zhu ZJ, Zhang HY, Yung WH, Ke Y (2014) Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer’s disease. Neurobiol Aging 35:1045–1054CrossRefPubMedGoogle Scholar
  27. 27.
    Qian ZM, Chang YZ, Zhu L, Yang L, Du JR, Ho KP, Wang Q, Li LZ, Wang CY, Ge X, Jing NL, Li L, Ke Y (2007) Development and iron-dependent expression of hephaestin in different brain regions of rats. J Cell Biochem 102:1225–1233CrossRefPubMedGoogle Scholar
  28. 28.
    Qian ZM, Wu XM, Fan M, Yang L, Du F, Yung WH, Ke Y (2011) Divalent metal transporter 1 is a hypoxia-inducible gene. J Cell Physiol 226:1596–1603CrossRefPubMedGoogle Scholar
  29. 29.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801CrossRefPubMedGoogle Scholar
  30. 30.
    Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59:278–292CrossRefPubMedGoogle Scholar
  31. 31.
    Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 104:13798–13803CrossRefPubMedGoogle Scholar
  32. 32.
    Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912CrossRefPubMedGoogle Scholar
  33. 33.
    Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin 1 identifies a conserved vertebrate iron exporter. Nature 403:776–781CrossRefPubMedGoogle Scholar
  34. 34.
    McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309CrossRefPubMedGoogle Scholar
  35. 35.
    Ganz T (2013) Systemic iron homeostasis. Physiol Rev 93:1721–1741CrossRefPubMedGoogle Scholar
  36. 36.
    Poli M, Asperti M, Ruzzenenti P, Regoni M, Arosio P (2014) Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front Pharmacol 5:86CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of NeuropharmacologyFudan University School of PharmacyShanghaiPeople’s Republic of China
  2. 2.Laboratory of Neuropharmacology, Institute of Translational and Precision MedicineNantong UniversityNantongPeople’s Republic of China
  3. 3.Department of Clinical Pharmacology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  4. 4.Research Center for Medicine and BiologyZunyi Medical UniversityZunyiPeople’s Republic of China

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