VDR Inverse Agonism by Metadichol Enhances VDBP-Mediated Immunity

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. Various Metadichol concentrations (1 pg/ml to 100 ng/ml) were applied to cells for 48 hours. ELISA measured 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: 81.73 ± 2.37 ng/ml; 8.36-fold increase in U937: 154.68 ± 3.19 ng/ml) while reducing LPS-induced inflammation. Metadichol shows dose-dependent immunomodulatory effects on VDBP release in human monocytic cells via VDR inverse agonism, outperforming traditional small molecule immunomodulators in immunological activation. The compound's VDR pathway modulation of 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.