Abstract
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.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcitriol / pharmacology*
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Cell Line
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Coculture Techniques
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Epithelial Cells / microbiology
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Female
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Humans
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Immunity, Innate*
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology*
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / metabolism
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Macrophages, Peritoneal / microbiology
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Male
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Mice
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Paracrine Communication / genetics
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Paracrine Communication / immunology*
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Receptors, Interleukin-1 Type I / genetics
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Receptors, Interleukin-1 Type I / immunology
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Receptors, Interleukin-1 Type I / metabolism
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Respiratory Mucosa / immunology
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / microbiology
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Respiratory Mucosa / pathology
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Tuberculosis / genetics
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Tuberculosis / immunology*
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Tuberculosis / metabolism
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Tuberculosis / pathology
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Vitamins / pharmacology*
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beta-Defensins / biosynthesis
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beta-Defensins / genetics
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beta-Defensins / immunology
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beta-Defensins / metabolism
Substances
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Carrier Proteins
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DEFB4A protein, human
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Defb4 protein, mouse
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IL1B protein, human
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IL1R1 protein, human
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IL1R1 protein, mouse
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, mouse
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Receptors, Interleukin-1 Type I
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Vitamins
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beta-Defensins
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Caspase 1
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Calcitriol