Turning VDR Off to Turn Immunity On: Metadichol Derepresses VDBP in Human Monocytes

Background: Vitamin D binding protein (VDBP) is a precursor to macrophage-activating factor (MAF) and regulates and controls innate immunity. Metadichol, a new nanoemulsion formulation that acts as an inverse agonist of the vitamin D receptor (VDR), was tested for its immunomodulatory effects on VDBP release in differentiated human monocytic cell lines. Methods: THP-1 and U937 monocytic cell lines were differentiated with PMA (20 ng/ml) and stimulated with LPS. Metadichol concentrations (1 pg/ml to 100 ng/ml) were applied to the cells for 48 hours. ELISAs were used to measure VDBP levels. Lipopolysaccharide stimulation significantly elevated VDBP release in both cell lines (10.19-fold in THP-1 cells: 117.01 +- 2.27 ng/ml; 12.03-fold in U937 cells: 222.56 +- 3.19 ng/ml vs. controls). Metadichol therapy altered VDBP release in a dose-dependent manner. Metadichol at 100 ng/ml significantly increased VDBP release (7.12-fold increase in THP-1 cells: 81.73 +- 2.37 ng/ml; 8.36-fold increase in U937 cells: 154.68 +- 3.19 ng/ml) while reducing LPS-induced inflammation. Metadichol has dose-dependent immunomodulatory effects on VDBP release in human monocytic cells via inverse VDR agonism, outperforming traditional small-molecule immunomodulators in immunological activation. The ability of the compound's VDR pathway to modulate VDBP levels without surpassing inflammatory thresholds suggests balanced immune response activation with potential therapeutic uses in immunological deficiency, cancer immunotherapy, and age-related immune decline