ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB

Cell Rep. 2013 Feb 21;3(2):386-400. doi: 10.1016/j.celrep.2013.01.009. Epub 2013 Feb 9.


Activation of the transcription factor NF-κB is essential for 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 has been lacking. Herein, we report that the zinc transporter SLC39A8 (ZIP8) is a transcriptional target of NF-κB and functions to negatively regulate proinflammatory responses through zinc-mediated down-modulation of IκB kinase (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 in conjunction with insufficient control of IKK. Our findings identify a negative feedback loop that directly regulates innate immune function through coordination of zinc metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transcriptional Activation
  • Zinc / metabolism*


  • Cation Transport Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • SLC39A8 protein, human
  • I-kappa B Kinase
  • Zinc