TLR2/1-induced IL-15 triggers a vitamin D3-dependent antimicrobial activity against Mycobacterium tuberculosis in human macrophages (44.5)

Abstract

Toll-like receptors (TLRs) are an integral component of the innate host defense, triggering macrophage differentiation by secretion of IL-15 and antimicrobial activity against intracellular M. tuberculosis through a vitamin D-dependent pathway. Here we investigate the mechanism by which TLR2/1 activates this antimicrobial pathway. We found that the TLR2/1-mediated induction of Cyp27B1 and VDR in human monocytes was dependent on secretion of IL-15. The direct activity of IL-15 to induce this pathway was examined in comparison to IL-4, since both induce monocytes to differentiate into CD209+ macrophages but with unique FcR expression. We found that IL-15 but not IL-4 was sufficient to induce Cyp27B1 and the VDR. The IL-15-derived macrophages upregulated Cyp27B1 activity as demonstrated by their ability to convert the vitamin D prohormone 25D3 to 1,25D3. Finally, in IL-15-derived macrophages, 25D3 triggered induction of the antimicrobial peptide cathelicidin and an antimicrobial activity against intracellular M. tuberculosis. Together, our data suggest that the TLR2/1 induction of the vitamin D-dependent antimicrobial pathway is dependent on the production and direct actions of IL-15.