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Zinc regulates expression of IL-23 p19 mRNA via activation of eIF2α/ATF4 axis in HAPI cells

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Abstract

Zinc (Zn2+) is considered to be one of the factors aggravating brain damage after cerebral ischemia. Since Zn2+ activates microglia, immune cells in the brain, this metal is proposed to modulate neuroinflammatory responses in the post-ischemic brain. Interleukin (IL)-23 is a heterodimeric cytokine composed of the p19 subunit unique to IL-23 and the p40 subunit common to IL-12. IL-23 has been shown to play a critical role in the progression of ischemic brain injury. However, whether Zn2+ participates in the expression of IL-23 in microglia remains unknown. In this study, we examined the effect of Zn2+ on IL-23 p19 mRNA expression using rat immortalized microglia HAPI cells. Exposure to Zn2+ dose- and time-dependently induced the expression of IL-23 p19 mRNA in HAPI cells. Inhibitors of MAPK and NF-κB pathways failed to suppress this induction. Interestingly, we found that Zn2+ stimulated the phosphorylation of eIF2α and promoted the nuclear accumulation of activating transcription factor 4 (ATF4). Treatment with salubrinal, an eIF2α dephosphorylation inhibitor, enhanced Zn2+-induced ATF4 accumulation and IL-23 p19 mRNA expression. In addition, reporter assay using the IL-23 p19 promoter region revealed that ATF4 directly transactivated IL-23 p19 promoter and that dominant-negative ATF4 suppressed Zn2+-induced activation of IL-23 p19 promoter. Taken together, these findings suggest that Zn2+ up-regulates expression of the IL-23 p19 gene via the eIF2α/ATF4 axis in HAPI cells.

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References

  • Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914

    Article  CAS  PubMed  Google Scholar 

  • Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21:6480–6491

    CAS  PubMed  Google Scholar 

  • Besser L, Chorin E, Sekler I, Silverman WF, Atkin S, Russell JT, Hershfinkel M (2009) Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus. J Neurosci 29:2890–2901

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115:1599–1608

    Article  CAS  PubMed  Google Scholar 

  • Christine CW, Choi DW (1990) Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons. J Neurosci 10:108–116

    CAS  PubMed  Google Scholar 

  • Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748

    Article  CAS  PubMed  Google Scholar 

  • Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB (2000) Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr 130:1471s–1483s

    CAS  PubMed  Google Scholar 

  • Fujiki K, Inamura H, Matsuoka M (2014) PI3K signaling mediates diverse regulation of ATF4 expression for the survival of HK-2 cells exposed to cadmium. Arch Toxicol 88:403–414

    Article  CAS  PubMed  Google Scholar 

  • Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V, Gaston JS (2010) Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A 107:17698–17703

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hara H, Kamiya T, Adachi T (2009) Zinc induces expression of the BH3-only protein PUMA through p53 and ERK pathways in SH-SY5Y neuroblastoma cells. Neurochem Res 34:1498–1506

    Article  CAS  PubMed  Google Scholar 

  • Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  CAS  PubMed  Google Scholar 

  • He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:20858–20865

    Article  CAS  PubMed  Google Scholar 

  • He K, Aizenman E (2010) ERK signaling leads to mitochondrial dysfunction in extracellular zinc-induced neurotoxicity. J Neurochem 114:452–461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Higashi Y, Segawa S, Matsuo T, Nakamura S, Kikkawa Y, Nishida K, Nagasawa K (2011) Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia. Glia 59:1933–1945

    Article  PubMed  Google Scholar 

  • Ho Y, Samarasinghe R, Knoch ME, Lewis M, Aizenman E, DeFranco DB (2008) Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death. Mol Pharmacol 74:1141–1151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hua F, Ma J, Ha T, Xia Y, Kelley J, Williams DL, Kao RL, Browder IW, Schweitzer JB, Kalbfleisch JH, Li C (2007) Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J Neuroimmunol 190:101–111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Inoue K, Branigan D, Xiong ZG (2010) Zinc-induced neurotoxicity mediated by transient receptor potential melastatin 7 channels. J Biol Chem 285:7430–7439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y, Ogawa Y (2014) Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes 63:152–161

    Article  CAS  PubMed  Google Scholar 

  • Kabu K, Yamasaki S, Kamimura D, Ito Y, Hasegawa A, Sato E, Kitamura H, Nishida K, Hirano T (2006) Zinc is required for Fc epsilon RI-mediated mast cell activation. J Immunol 177:1296–1305

    Article  CAS  PubMed  Google Scholar 

  • Kauppinen TM, Higashi Y, Suh SW, Escartin C, Nagasawa K, Swanson RA (2008) Zinc triggers microglial activation. J Neurosci 28:5827–5835

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim SM, Yoon SY, Choi JE, Park JS, Choi JM, Nguyen T, Kim DH (2010) Activation of eukaryotic initiation factor-2 alpha-kinases in okadaic acid-treated neurons. Neuroscience 169:1831–1839

    Article  CAS  PubMed  Google Scholar 

  • Kim YM, Reed W, Wu W, Bromberg PA, Graves LM, Samet JM (2006) Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 290:1028–1035

    Article  Google Scholar 

  • Knoch ME, Hartnett KA, Hara H, Kandler K, Aizenman E (2008) Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge. Glia 56:89–96

    Article  PubMed Central  PubMed  Google Scholar 

  • Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–1016

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Ouyang X, Yang J, Liu J, Li Q, Gu Y, Fukata M, Lin T, He JC, Abreu M, Unkeless JC, Mayer L, Xiong H (2009) AP-1 activated by toll-like receptors regulates expression of IL-23 p19. J Biol Chem 284:24006–24016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lu PD, Harding HP, Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167:27–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lv M, Liu Y, Zhang J, Sun L, Liu Z, Zhang S, Wang B, Su D, Su Z (2011) Roles of inflammation response in microglia cell through Toll-like receptors 2/interleukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience 176:162–172

    Article  CAS  PubMed  Google Scholar 

  • Mise-Omata S, Kuroda E, Niikura J, Yamashita U, Obata Y, Doi TS (2007) A proximal kappaB site in the IL-23 p19 promoter is responsible for RelA- and c-Rel-dependent transcription. J Immunol 179:6596–6603

    Article  CAS  PubMed  Google Scholar 

  • Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101:451–454

    Article  CAS  PubMed  Google Scholar 

  • Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Qi X, Hosoi T, Okuma Y, Kaneko M, Nomura Y (2004) Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol 66:899–908

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  • Sensi SL, Canzoniero LM, Yu SP, Ying HS, Koh JY, Kerchner GA, Choi DW (1997) Measurement of intracellular free zinc in living cortical neurons: routes of entry. J Neurosci 17:9554–9564

    CAS  PubMed  Google Scholar 

  • Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH (1999) Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci U S A 96:2414–2419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A (2012) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18:911–917

    Article  CAS  PubMed  Google Scholar 

  • Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–950

    Article  CAS  PubMed  Google Scholar 

  • Sun XY, Wei YP, Xiong Y, Wang XC, Xie AJ, Wang XL, Yang Y, Wang Q, Lu YM, Liu R, Wang JZ (2012) Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). J Biol Chem 287:11174–11182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takeda A (2001) Zinc homeostasis and functions of zinc in the brain. Biometals 14:343–351

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Wang X, Zhang S, Qu G, Liu S (2013) A protective role of heme-regulated eIF2alpha kinase in cadmium-induced toxicity in erythroid cells. Food Chem Toxicol 62:880–891

    Article  CAS  PubMed  Google Scholar 

  • Weinstein JR, Koerner IP, Moller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Weiss JH, Hartley DM, Koh JY, Choi DW (1993) AMPA receptor activation potentiates zinc neurotoxicity. Neuron 10:43–49

    Article  CAS  PubMed  Google Scholar 

  • Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, Kurosaki T, Yamashita S, Tokunaga M, Nishida K, Hirano T (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  CAS  PubMed  Google Scholar 

  • Zeng L, Liu YP, Sha H, Chen H, Qi L, Smith JA (2010) XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages. J Immunol 185:2324–2330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang C, Bai N, Chang A, Zhang Z, Yin J, Shen W, Tian Y, Xiang R, Liu C (2013) ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes. Cell Mol Immunol 10:84–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhong L, Wang L, Xu L, Liu Q, Jiang L, Zhi Y, Lu W, Zhou P (2014) The role of nitric oxide synthase signaling pathway in the Zn-induced cellular responses in MCF-7 cells. Environ Toxicol Pharmacol 38:783–791

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (to H.H.; No. 26460630).

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  1. Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan

    Takuya Doi, Hirokazu Hara, Miho Kajita, Tetsuro Kamiya & Tetsuo Adachi

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  1. Takuya Doi
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  2. Hirokazu Hara
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Correspondence to Hirokazu Hara.

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Doi, T., Hara, H., Kajita, M. et al. Zinc regulates expression of IL-23 p19 mRNA via activation of eIF2α/ATF4 axis in HAPI cells. Biometals 28, 891–902 (2015). https://doi.org/10.1007/s10534-015-9874-4

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