1α,25-Dihydroxyvitamin D₃ upregulates HIF-1 and TREM-1 via mTOR signaling

Triggering receptor expressed on myeloid cells-1 (TREM-1) is induced by 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) in human monocytes/macrophages and epithelial cells. However, little information is available regarding the mechanism of 1,25(OH)₂D₃-induced TREM-1 expression in human monocytes/macrophages. In this study, 1,25(OH)₂D₃ was shown to strongly upregulate hypoxia-inducible transcription factor (HIF) in PMA-differentiated U937 cells. However, HIF was not mainly involved in 1,25(OH)₂D₃-induced TREM-1 expression. Instead, 1,25(OH)₂D₃-induced expression of TREM-1 was inhibited by rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, indicating the involvement of mTOR. Induction of HIF proteins by 1,25(OH)₂D₃ was also inhibited by rapamycin. In addition, 1,25(OH)₂D₃ induced the phosphorylation of p70S6 kinase, a target of mTOR complex 1 (mTORC1). Our results suggest that 1,25(OH)₂D₃ induces the expression of TREM-1 through the mTOR signaling pathway in human macrophages.