calcitriol and Hypersensitivity

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.

Topics: Animals; Cell Line; Cytokines; Enzyme Activation; Feedback, Physiological; Gene Expression Regulation; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophages; Mice; Mice, Knockout; MicroRNAs; Models, Biological; NF-kappa B; Receptors, Calcitriol; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Toll-Like Receptors; Transcription, Genetic; Vitamin D

Topics: Humans; Hypersensitivity; Nutritional Physiological Phenomena; Terminology as Topic; Vitamin D