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.

The molecular basis of chaperone-mediated interleukin 23 assembly control

“…Zinc plays pivotal roles in regulating the immune system 51 . Furthermore, it has been shown that zinc upregulates IL-23α mRNA expression 52 . Thus, zinc may not only affect IL-23α on a transcriptional level but could potentially also influence its maturation.…”

Prophylactic Zinc and Therapeutic Selenium Administration Increases the Antioxidant Enzyme Activity in the Rat Temporoparietal Cortex and Improves Memory after a Transient Hypoxia‐Ischemia

“…Several mechanisms can be accounted for the latter effect. For instance, the decrease in interleukin-1 (IL-1) and IL-23 expression [ 4 ], increase in chemokine and growth factor levels [ 5 ], and decrease in oxidative stress are because of the antioxidant activity of Cu and Zn superoxide dismutase (SOD1 and 3) [ 6 ]. However, excessive accumulation of zinc can also cause neuronal degeneration in the hippocampus and cerebral cortex [ 7 ].…”

Influence of extracellular zinc on M1 microglial activation

“…On the other hand, in many pathological conditions such as ischaemia and hypoglycaemia, massive amounts of zinc are released, which then accumulate in postsynaptic neurons, resulting in neuronal cell death 3 4 5 . Recent studies have revealed that extracellular zinc acts to prevent the uptake of glutamate into astrocytes and induce interleukin (IL)-23 expression in a dose-dependent manner, suggesting that presynaptic zinc release mediates the progression of the aforementioned disorders by regulating glial cell functions as well as neuronal cell death 6 7 .…”