γ-Interferon-Induced Resistance to 1,25-(OH)2D3in Human Monocytes and Macrophages: A Mechanism for the Hypercalcemia of Various Granulomatoses1

The hypercalcemia of various granulomatoses is caused by endogenous 1,25-dihydroxyvitamin D [1,25-(OH) 2 D 3 ] overproduction by disease-activated macrophages.The inability of 1,25(OH) 2 D 3 to suppress its synthesis in macrophages contrasts with the tight control of its production in macrophage precursors, peripheral blood monocytes (PBM).We examined whether 1,25(OH) 2 D 3 resistance develops as PBM differentiate to macrophages or with macrophage activation.Normal human pulmonary alveolar macrophages (PAM) are less sensitive to 1,25(OH) 2 D 3 than PBM, despite similar vitamin D receptor content; however, both PBM and PAM respond to exogenous 1,25-(OH) 2 D 3 by inhibiting 1,25(OH) 2 D 3 synthesis and inducing 1,25(OH) 2 D 3 degradation through enhancement of 24-hydroxylase mRNA levels and activity.The human monocytic cell line THP-1 mimics PAM in 1,25(OH) 2 D 3 synthesis and sensitivity to exogenous 1,25(OH) 2 D 3 .We utilized THP-1 cells to examine the response to 1,25(OH) 2 D 3 with macrophage activation.Activation of THP-1 cells with ␥-interferon (␥-IFN) enhances 1,25(OH) 2 D 3 synthesis 30-fold, blocks 1,25-(OH) 2 D 3 suppression of its synthesis, and reduces by 42.2% 1,25-(OH) 2 D 3 induction of its degradation.The antagonistic effects of ␥-IFN are not merely restricted to enzymatic activities.In THP-1 cells and in normal PBM, ␥-IFN inhibits 1,25-(OH) 2 D 3 induction of 24-hydroxylase mRNA levels without reducing mRNA stability, suggesting ␥-IFN inhibition of 1,25(OH) 2 D 3 transactivating function.These results explain 1,25(OH) 2 D 3 overproduction in granulomatoses and demonstrate potent inhibition by ␥-IFN of 1,25(OH) 2 D 3 action in immune cells.(