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.

The past decade, particularly the last 18 months, witnessed a vigorous increase in interest in vitamin D from both the lay and biomedical worlds. Much of the growing interest in vitamin D is powered by new data being extracted from the National Health and Nutrition Examination Survey (NHANES). The newest statistics demonstrate that more than 90% of the pigmented populace of the United States (Blacks, Hispanics, and Asians) now suffer from vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml), with nearly three fourths of the white population in this country also being vitamin D insufficient. This represents a near doubling of the prevalence of vitamin D insufficiency seen just 10 yr ago in the same population. This review attempts to provide some explanation for: 1) the rapid decline in vitamin D status in the United States; 2) the adverse impact of vitamin D insufficiency on skeletal, infectious/inflammatory, and metabolic health in humans; and 3) the therapeutic rationale and reliable means for vigorous supplementation of our diets with vitamin D.