Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response

In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection. Keywords: timecourse, cell type comparison The monocyte microarrays were generated using primary human monocytes stimulated with a TLR2/1L or media at 0, 3, 6, 12, 24 hour timepoints. A total of 10 donors were used with time 0 h samples prepared for each. For time points, we used cells from 4 of the 10 donors to prepare media and TLR2/1-stimulated samples. Dendritic cells were generated by culturing primary human monocytes with GM-CSF (800 U/ml) and IL-4 (1000 U/ml) for 7 days. The cells were then harvested and recultured for 12 hours with TLR2/1L or media. A total of four donors were used. See manuscript for specific details on data analysis and experimental design and reagents.