Abstract
The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25[OH]2D3) modulates innate immune response, but the mechanism remains poorly understood. In this article, we report that vitamin D receptor signaling attenuates TLR-mediated inflammation by enhancing the negative feedback inhibition. Vitamin D receptor inactivation leads to hyperinflammatory response in mice and macrophage cultures when challenged with LPS, because of microRNA-155 (miR-155) overproduction that excessively suppresses suppressor of cytokine signaling 1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates suppressor of cytokine signaling 1 by downregulating miR-155. 1,25(OH)2D3 downregulates bic transcription by inhibiting NF-κB activation, which is mediated by a κB cis-DNA element located within the first intron of the bic gene. Together, these data identify a novel regulatory mechanism for vitamin D to control innate immunity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Cytokines / immunology
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Cytokines / metabolism
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Enzyme Activation / drug effects
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Feedback, Physiological / drug effects
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Gene Expression Regulation / drug effects
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Humans
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Hypersensitivity / genetics
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Hypersensitivity / immunology
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharides / immunology
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Macrophages / drug effects*
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Macrophages / metabolism*
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Mice
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Mice, Knockout
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MicroRNAs / genetics*
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Models, Biological
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NF-kappa B / metabolism
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Receptors, Calcitriol / genetics
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Receptors, Calcitriol / metabolism
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Signal Transduction / drug effects*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics*
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Toll-Like Receptors / metabolism*
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Transcription, Genetic / drug effects
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Vitamin D / analogs & derivatives*
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Vitamin D / pharmacology
Substances
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Cytokines
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Inflammation Mediators
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Lipopolysaccharides
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MicroRNAs
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Mirn155 microRNA, mouse
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NF-kappa B
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Receptors, Calcitriol
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptors
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Vitamin D
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1,25-dihydroxyvitamin D