title: Zinc regulates expression of IL-23 p19 mRNA via activation of eIF2α/ATF4 axis in HAPI cells.
abstract: Zinc (Zn(2+)) is considered to be one of the factors aggravating brain damage after cerebral ischemia. Since Zn(2+) 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 Zn(2+) participates in the expression of IL-23 in microglia remains unknown. In this study, we examined the effect of Zn(2+) on IL-23 p19 mRNA expression using rat immortalized microglia HAPI cells. Exposure to Zn(2+) 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 Zn(2+) stimulated the phosphorylation of eIF2α and promoted the nuclear accumulation of activating transcription factor 4 (ATF4). Treatment with salubrinal, an eIF2α dephosphorylation inhibitor, enhanced Zn(2+)-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 Zn(2+)-induced activation of IL-23 p19 promoter. Taken together, these findings suggest that Zn(2+) up-regulates expression of the IL-23 p19 gene via the eIF2α/ATF4 axis in HAPI cells.
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Doi
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan. harah@gifu-pu.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kajita
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002934:Cinnamates / Q000008:administration & dosage; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives; D015032:Zinc / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: C497110:Atf4 protein, rat; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D053760:Interleukin-23 Subunit p19; D012333:RNA, Messenger; C496827:salubrinal; D051701:Activating Transcription Factor 4; D013890:Thiourea; D015032:Zinc
keywords: Activating transcription factor 4; IL-23; Microglia; Phosphorylation; Zinc; eIF2α