ABSTRACT
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.
Subject(s)
Cation Transport Proteins/metabolism , NF-kappa B/antagonists & inhibitors , Zinc/metabolism , Animals , Base Sequence , Binding Sites , Cation Transport Proteins/antagonists & inhibitors , Cation Transport Proteins/genetics , 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/genetics , NF-kappa B/metabolism , Promoter Regions, Genetic , RNA Interference , RNA, Small Interfering/metabolism , Transcriptional ActivationABSTRACT
The effect a solvent has on the photophysical properties of a series of benzophenone derivatives, all FDA approved for use in sunscreens, is examined. Experimentally significant differences in the solvatochromic behavior are found to be dependent upon the substituents on the parent benzophenone molecule. The spectral trends do not appear to originate from only changes in the solvent polarity but indicate that specific solvent-solute interactions influence the absorbance energies of some benzophenones. Computational investigations examine the structure and electronic excitation energies of the molecules. Specific interactions of the solvent and solute are modeled to evaluate structural changes that result from solvent-solute complexation and the impact of the changes upon absorbance properties. The viability of an intramolecular excited state proton transfer is theoretically evaluated. The combination of experimental and computational analysis provides a more complete understanding of the molecular level origin of the unique photophysical properties of this class of UV absorbers.
