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Activation of the transcription factor NF-κB is essential to innate immune function and requires strict regulation. The micronutrient zinc modulates proper host defense and zinc deficiency is associated with elevated inflammation and worse outcomes in response to bacterial infection and sepsis. Previous studies suggest that zinc may regulate NF-κB activity during innate immune activation but a mechanistic basis to support this is lacking. Herein we report that the zinc transporter, SLC39A8 (ZIP8), is a transcriptional target of NF-κB and functions to negatively regulate pro-inflammatory responses through zinc-mediated down-modulation of IKK activity in vitro. Accordingly, fetal fibroblasts obtained from Slc39a8 hypomorphic mice exhibited dysregulated zinc uptake and increased NF-κB activation. Consistent with this, mice provided zinc-deficient dietary intakes developed excessive inflammation to polymicrobial sepsis …