Vitamin D3–Triggered Antimicrobial Response—Another Pleiotropic Effect beyond Mineral and Bone Metabolism

Abstract

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...

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

“…This was followed by subsequent description of 'non-classical functions of vitamin D', which include immunomodulatory properties of vitamin D, firmly supported by numerous in vitro and animal experiments (Bouillon et al, 2008). The in vitro findings consistently suggest that vitamin D enhances antimicrobial activity at early stages of infection (Liu et al, 2006;Urry et al, 2009) and provides negative feedback at later stages (Sadeghi et al, 2006). The inhibitory effects of vitamin D on adaptive immune response include induction of the potent antiinflammatory cytokine IL-10.…”

Extra-renal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease

“…In DCs localized production of 1,25(OH) 2 D 3 may affect proliferation and phenotype of adjacent T-cells but it is also able to exert autocrine effects by suppressing DC maturation and maintaining these cells in a more tolerogenic state [27]. Like DCs, macrophages are also able to present antigen and influence acquired immune responses but we have recently shown that the most likely function of 1␣-hydroxylase in these cells is to stimulate innate immunity [29]. In this study expression of 1␣-OHase by monocytes was induced as a result of ligand binding to TLR2 but the enzyme was only functional if sufficient substrate (25OHD 3 ) was available for conversion to 1,25(OH) 2 D 3 .…”

Dual antiplasmodial activity of vitamin D3 and its analog, 22-oxacalcitriol, by direct and indirect mechanisms

“…Instead, there are numerous reports showing the potential of VD to inhibit microorganism proliferation [15][16][17][18][19][20], particularly in the case of tuberculosis and other mycobacterial infections [21][22][23][24].…”