Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection

Vitamin D was discovered as the cure for nutritional rickets. Classically, hormonal 1,25-dihydroxyvitamin D (1,25D), produced in the kidney by CYP27B1-catalyzed 1α-hydroxylation from its circulating 25-hydroxy precursor, has been considered to function as a critical endocrine regulator of calcium homeostasis. However, our appreciation of vitamin D metabolism and physiological function has evolved dramatically in recent years. First, vitamin D is now recognized as a pleiotropic regulator of human physiology, with emerging roles in cancer chemoprevention, cardio-protection, and, in particular, regulation of immune system functions. Moreover, CYP27B1 is very widely expressed, and evidence is rapidly accumulating that local CYP27B1-catalyzed production of 1,25D, controlled by tissue-specific signals, is critical for its physiological actions. Nowhere is this more apparent than in the innate immune system, where recent studies have shown that CYP27B1 expression is under control of several immune signaling pathways, and that signaling by 1,25D in macrophages and dendritic cells is critical for innate immune responses to infection. This review will describe our current knowledge of the signaling pathways that lead to 1,25D production in the immune system and the downstream signaling events it controls in response to pathogen recognition.