Journal
INFLAMMATION RESEARCH
Volume 62, Issue 2, Pages 133-143Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00011-012-0559-y
Keywords
Lipopolysaccharide; Macrophages; Zip14; SLC39A14; Zinc transporter
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Funding
- Biomedical Research Council, Agency for Science, Technology and Research, Singapore
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We investigated the role and regulation of zinc transporters in the activation of the inflammatory response in macrophages. Our exploratory computational study found that Zip14 (SLC39A14) was consistently up-regulated in activated macrophages; we therefore focused subsequently on that gene in the mechanistic study. The expression and function of Zip14 was assessed in primary macrophages obtained by in-vitro differentiation of monocytes from human blood. Primary macrophages were subjected to treatments with lipopolysaccharides, cytokines, chemicals, and pharmacological agents. SLC39A14 and inflammatory cytokine gene expressions were assessed by RT-qPCR. Zip14 siRNA knockdown was performed to explore the gene function. Lipopolysaccharide's inflammatory stimulus was a strong inducer of SLC39A14 mRNA expression in macrophages. This induction was dependent on calcium signaling, GC-rich DNA-binding, and NF-kappa B down-regulation. Impregnation of lipopolysaccharide-stimulated macrophages with the glucocorticoid dexamethasone further enhanced Zip14 expression while reducing interleukin-6 and tumor necrosis factor-alpha production. Zip14 knockdown in macrophages attenuated the expression and secretion of cytokines, indicating a buffering function for this zinc transporter. Collectively, our results identified the zinc transporter Zip14 as expressed downstream of lipopolysaccharide signals in macrophages. Zip14 induction had a regulatory function in cytokine production.
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