gamma -interferon-induced resistance to 1,25-(OH) sub(2) D sub(3) in human monocytes and macrophages: A mechanism for the hypercalcemia of various granulomatoses

• Published in: The journal of clinical endocrinology and metabolism Vol. 82; no. 7; pp. 2222 - 2232
• Main Authors: Dusso, A S, Kamimura, S, Gallieni, M, Zhong, M, Negrea, L, Shapiro, S, Slatopolsky, E
• Format: Journal Article
• Language: English
• Published: 01.01.1997
• ISSN: 0021-972X

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