The zinc transporter SLC39A8 is a novel negative feedback regulator of the NF-κB pathway and innate immune activation (116.33)

Zinc is an essential micronutrient required for proper immune function. We previously reported that zinc deficiency increases inflammation and mortality in response to polymicrobial sepsis. Here we report that a specific zinc transporter, SLC39A8 (ZIP8), is a transcriptional target of NF-κB and functions as a negative regulator of NF-κB. Initially we observed that TNFα or LPS inducesSLC39A8 expression in human monocytes, macrophages and lung epithelial cells, leading to an increase in intracellular zinc. We then identified a functional NF-κB binding site in the promoter region that triggers ZIP8 expression. Silencing of ZIP8 expression significantly decreased intracellular accumulation of zinc and increased the inflammatory response, as determined by increased cytokine production and phosphorylation of IκBα, P65, ERK and Akt. We further revealed that zinc directly inhibits IKKβ in a ZIP8-dependent manner. In mice, endotoxin or cecal ligation and puncture resulted in increased ZIP8 expression and zinc uptake in circulating monocytes and lung tissue, contributing to hypozincemia. Consistent with these observations, mouse embryonic fibroblasts obtained from Slc39a8 hypomorphic mice were more responsive to TNFα and IL-1β compared to wild-type cells, confirming the function of ZIP8 as a negative regulator of NF-κB and innate immune activation. Taken together, our findings identify a novel inducible inhibitory feedback pathway for NF-κB and the pro-inflammatory response.