Nutrient isothiocyanates covalently modify and inhibit the inflammatory cytokine macrophage migration inhibitory factor (MIF).
Dietary ITCs (isothiocyanates) prevent cancer and show other bioactivities in vivo. As electrophiles, ITCs may covalently modify cellular proteins. Using a novel proteomics screen, we identified MIF (macrophage migration inhibitory factor) as the principal target of nutrient ITCs in intact cells. ITCs covalently modify the N-terminal proline residue of MIF and extinguish its catalytic tautomerase activity. MIF deficiency does not prevent induction of Phase 2 gene expression, a hallmark of many cancer chemopreventives, including ITCs. Due to the emerging role of MIF in the control of malignant cell growth and its clear involvement in inflammation, inhibition of MIF by nutrient ITCs suggests therapeutic strategies for inflammatory diseases and cancer.
Cross
Janet V
JV
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. cross@virginia.edu
Rady
Joshua M
JM
Foss
Frank W
FW
Lyons
Charles E
CE
Macdonald
Timothy L
TL
Templeton
Dennis J
DJ
D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D017879:Isothiocyanates / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational
D017879:Isothiocyanates; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human