Vitamin D Induces Interleukin-1β Expression: Paracrine Macrophage Epithelial Signaling Controls M. tuberculosis Infection

Although vitamin d deficiency is a common feature among patients presenting with active tuberculosis,the full scope of vitamin d action during mycobacterium tuberculosis (mtb) infection is poorly understood. as macrophages are the primary site of mtb infection and are sites of vitamin d signaling,we have used these cells to understand the molecular mechanisms underlying modulation of the immune response by the hormonal form of vitamin d,1,25-dihydroxyvitamin d (1,25d). we found that the virulent mtb strain h37rv elicits a broad host transcriptional response. transcriptome profiling also revealed that the profile of target genes regulated by 1,25d is substantially altered by infection,and that 1,25d generally boosts infection-stimulated cytokine/chemokine responses. we further focused on the role of 1,25d- and infection-induced interleukin 1β (il-1β) expression in response to infection. 1,25d enhanced il-1β expression via a direct transcriptional mechanism. secretion of il-1β from infected cells required the nlrp3/caspase-1 inflammasome. the impact of il-1β production was investigated in a novel model wherein infected macrophages were co-cultured with primary human small airway epithelial cells. co-culture significantly prolonged survival of infected macrophages,and 1,25d/infection-induced il-1β secretion from macrophages reduced mycobacterial burden by stimulating the anti-mycobacterial capacity of co-cultured lung epithelial cells. these effects were independent of 1,25d-stimulated autophagy in macrophages but dependent upon epithelial il1r1 signaling and il-1β-driven epithelial production of the antimicrobial peptide defb4/hbd2. these data provide evidence that the anti-microbial actions of vitamin d extend beyond the macrophage by modulating paracrine signaling,reinforcing its role in innate immune regulation in humans. © 2013 verway et al.