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J Steroid Biochem Mol Biol. 2014 Oct;144 Pt A:81-6. doi: 10.1016/j.jsbmb.2013.09.014. Epub 2013 Oct 5.

MicroRNA-mediated mechanism of vitamin D regulation of innate immune response.

Author information

1
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA. Electronic address: cyan@medicine.bsd.uchicago.edu.
2
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
3
Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Abstract

Macrophages play a critical role in innate immune response to protect the host from pathogenic microorganisms. Inflammatory response is regulated by negative feedback mechanisms to prevent detrimental effects. The SOCS family of proteins is key component of the negative feedback loop that regulates the intensity, duration and quality of cytokine signaling, whereas miR-155 is a key regulator of Toll-like receptor (TLR) signaling that targets SOCS1 in activated macrophages to block the negative feedback loop. Recently we showed that 1,25-dihydroxyvitamin D (1,25(OH)2D3) modulates innate immune response by targeting the miR-155-SOCS1 axis. We found that Vdr deletion leads to hyper inflammatory response in mice and macrophage cultures when challenged with lipopolysaccharide (LPS), due to miR-155 overproduction to excessively suppress SOCS1. Using mice with bic/miR-155 deletion we confirmed that 1,25(OH)2D3 suppresses inflammation and stimulates SOCS1 by down-regulating miR-155. Mechanistically 1,25(OH)2D3 down-regulates bic transcription by blocking NF-κB activation, which is mediated by a κB cis-DNA element identified within the first intron of the bic gene. At the molecular level, we demonstrated that VDR inhibits NF-κB activation by directly interacting with IKKβ protein. Our studies identified a novel mechanism whereby VDR signaling attenuates TLR-mediated inflammation by enhancing the negative feedback regulation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

KEYWORDS:

IKKβ; Inflammation; Macrophage; NF-kappaB; Negative feedback loop; SOCS1; Vitamin D; miR-155

PMID:
24103701
PMCID:
PMC3976893
DOI:
10.1016/j.jsbmb.2013.09.014
[Indexed for MEDLINE]
Free PMC Article
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