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.
Toll‐like receptors mediate the activation of critical host defense mechanisms such as cytokine/chemokine secretion and a vitamin D‐dependent anti‐microbial pathway in response to pathogens. Here we investigated whether TLR8, which mediates cellular activation by HIV‐1 ssRNA, triggers these two key defense mechanisms in human monocytes. We found that HIV‐1 ssRNA and a synthetic TLR8 ligand stimulates monocytes to secrete IL‐12 as well as the CCR5 ligands RANTES, MIP1α and MIP1β. Furthermore, HIV‐1 ssRNA triggered gene expression of two critical components of the vitamin D‐dependent anti‐microbial pathway, CYP27b1 (1‐α hydroxylase) and the vitamin D receptor, which together enables monocytes to induce gene expression of the anti‐microbial peptide cathelicidin. Pretreatment of HIV‐1 with cathelicidin peptide directly inhibited HIV‐1 infectivity. Finally, the active vitamin D hormone 1,25‐dihydroxyvitamin D3 triggered cathelicidin gene expression in HIV‐1 infected monocytes and induced an anti‐viral activity against HIV‐1. The 1,25D3‐induced anti‐viral activity was ablated by a cathelicidin specific siRNA. In conclusion, activation of human monocytes with HIV‐1 ssRNA triggers 1) release of cytokines/chemokines with known roles in HIV host defense and 2) a vitamin D‐dependent anti‐viral pathway that is mediated by cathelicidin.
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