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.

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N iels Ryberg Finsen, who received the third Nobel prize in medicine in 1903, was honored because in 1895 he had discovered a cure for a disease that had been incurable before, i.e., skin tuberculosis known as lupus vulgaris (1-3). Phototherapy was performed by exposing the skin to an electrical arc lamp and producing moderate sunburn. Although alternative or complementary mechanisms have been proposed, such as generation of singlet oxygen by the porphyrin molecules in Mycobacterium tuberculosis, it appears that after more than 100 years the main molecular mechanism underlying Finsen's phototherapy has been unraveled (4) and turns out to be one more of the pleiotropic effects of vitamin D 3 through genomic and nongenomic pathways (5-7).To better understand the following, some background information is useful. If an organism is invaded by an infectious agent, the organism does rely not only on the acquired immune system (mainly antibodies and lymphocytes), but as an additional acute emergency intervention it relies also on the phylogenetically ancient innate immune system, which depends on different Toll-like receptors (TLR). Based on the recognition of specific repetitive patterns (8) in the chemical structure of the invading microorganisms' products, e.g., lipopeptides (9), the corresponding TLR is activated and triggers the synthesis of cationic antimicrobial peptides (10,11) such as cathelicidin (4) and ␣-or ␤-defensins (12). The human cathelicidin contains a C-terminal cationic, antimicrobial peptide domain that is activated by cleavage from the N-terminal cathelin portion of the propeptide, which is stored in secondary granules of neutrophils and other white cell populations. Production and secretion of cathelicidin is not restricted to myeloid cells, however. It occurs also in other cells exposed to microbes, such as the epithelial cells of the mouth, tongue, esophagus, intestine, cervix and vagina (13), lung (14), and salivary, sweat (15), and mammary glands (16).Liu et al. (4) pursued a remarkable species difference: In mice it had been shown that the acute antimicrobial response triggered by the heterodimer TLR2/1 depends on the generation of nitric oxide (NO) (17), yet in human macrophages the antimicrobial activity of macrophages triggered by TLR 2/1 is not dependent on the generation of NO and obviously must be mediated by alternative effectors. Studies to resolve this puzzle led to an unanticipated result that extends the range of the known effects of active vitamin D 3 , at least in humans-a further addition to a growing list of actions of active vitamin D 3 beyond mineral and bone metabolism.Using intracellular M. tuberculosis, it had been shown (18) that activation of the heterodimer TLR1/2 reduced its viability in human monocytes and macrophages, but not in dendritic cells. Liu et al. went one step further and investigated gene expression profiles of monocytes (and of dendritic cells as controls) after exposure to a synthetic M. tuberculosis-specific lipopeptide acting via the heterodimer TLR2/1...