GAMMA-INTERFERON-INDUCED RESISTANCE TO 1,25-(OH)(2)D-3 IN HUMAN MONOCYTES AND MACROPHAGES - A MECHANISM FOR THE HYPERCALCEMIA OF VARIOUS GRANULOMATOSES

The hypercalcemia of various granulomatoses is caused by endogenous 1, 25-dihydroxyvitamin D [1,25-(OH)2(D3)] overproduction by disease-activ ated macrophages. The inability of 1,25(OH)(2)D-3 to suppress its synt hesis in macrophages contrasts with the tight control of its productio n in macrophage precursors, peripheral blood monocytes (PBM). We exami ned whether 1,25(OH)(2)D-3 resistance develops as PBM differentiate to macrophages or with macrophage activation. Normal human pulmonary alv eolar 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 syn thesis 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 exoge nous 1,25(OH)(2)D-3. We utilized THP-1 cells to examine the response t o 1,25(OH)(2)D-3 with macrophage activation. Activation of THP-1 cells with gamma-interferon (gamma-IFN) enhances 1,25(OH)(2)D-3 synthesis 3 0-fold, blocks 1,25-(OH)(2)D-3 suppression of its synthesis, and reduc es by 42.2% 1,25-(OH)(2)D-3 induction of its degradation. The antagoni stic effects of gamma-IFN are not merely restricted to enzymatic activ ities. In THP-1 cells and in normal PBM, gamma-IFN inhibits 1,25-(OH)( 2)D-3 induction of 24-hydroxylase mRNA levels without reducing mRNA st ability, suggesting gamma-IFN inhibition of 1,25(OH)(2)D-3 transactiva ting function. These results explain 1,25(OH)(2)D-3 overproduction in granulomatoses and demonstrate potent inhibition by gamma-IFN of 1,25( OH)(2)D-3 action in immune cells.