, Volume 28, Issue 5, pp 891–902 | Cite as

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

  • Takuya Doi
  • Hirokazu Hara
  • Miho Kajita
  • Tetsuro Kamiya
  • Tetsuo Adachi


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.


Zinc IL-23 Microglia Activating transcription factor 4 eIF2α Phosphorylation 



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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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Takuya Doi
    • 1
  • Hirokazu Hara
    • 1
  • Miho Kajita
    • 1
  • Tetsuro Kamiya
    • 1
  • Tetsuo Adachi
    • 1
  1. 1.Laboratory of Clinical PharmaceuticsGifu Pharmaceutical UniversityGifuJapan

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