Vitamin D Inhibits Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase-1

Abstract

It is estimated that one billion people around the world are vitamin D deficient. Vitamin D deficiency has been linked to various inflammatory diseases. However, the mechanism by which vitamin D reduces inflammation remains poorly understood. In this study, we investigated the inhibitory effects of physiologic levels of vitamin D on lipopolysaccharide (LPS)-stimulated inflammatory response in human blood monocytes, and explored potential mechanisms of vitamin D action. We observed that two forms of the vitamin D, 1,25(OH)2D3, and 25(OH)D3, dose dependently inhibited LPS-induced p38 phosphorylation at physiologic concentrations, IL-6 and TNF-α production by human monocytes. Upon vitamin D treatment, the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was significantly upregulated in human monocytes and murine bone marrow-derived macrophages (BMM). Increased binding of the vitamin D receptor and increased histone H4 acetylation at the identified vitamin D response element of the murine and human MKP-1 promoters were demonstrated. Moreover, in BMM from MKP1−/− mice, the inhibition of LPS-induced p38 phosphorylation by vitamin D was completely abolished. Vitamin D inhibition of LPS-induced IL-6 and TNF-α production by BMM from MKP-1−/− mice was significantly reduced as compared to wild type mice. In conclusion, this study identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages.

Assessment of Vitamin D status In Patients of Chronic Low Back Pain of Unknown Etiology

“…Vitamin D deficient people have much higher levels of inflammatory markers than those that get enough vitamin D. Adequate vitamin D decreases this inflammation and has been shown to alleviate lower back pain. Up-regulation of MKP-1 by vitamin D is the novel pathway by which vitamin D inhibits LPSinduced p38 activation and cytokine production in monocytes/macrophages [16]. RANK-RANKL osteoprotegerin system, modulated by vitamin D, directly influences the release of pro inflammatory cytokines.…”

Optimal vitamin D levels in Crohn's disease: a review

“…Evidence suggests that vitamin D increases tight junction proteins and enhances gut mucosal healing post-injury (77) . For example, following exposure to dextran sulphate sodium, a chemical which induces colitis, the VDR knock out mice were unable to maintain the integrity of the epithelial barrier (69,78) and had lower expression of tight junction proteins than in wild-type mice (77)(78)(79) . As a result of reduced tight junction proteins, vitamin D-deficient and VDR knock out mice had increased gut permeability compared with vitamin D-sufficient wild-type mice (78) .…”

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

“…The presence of VDRs in human T lymphocytes [Provvedini et al 1983;Baeke et al 2010], in greater number in CD8 than in CD4 lymphocytes [Vedman et al 2000], as well as in B lymphocytes [Provvedini et al 1983;Chen et al 2007], and the expression of CYP27B1 in lymph nodes [Zehdner et al 2001] and T lymphocytes [Sigmundsdottir et al 2007] constitute important indications of a potential role of vitamin D in adaptive immunity. Furthermore, a number of mechanisms by which vitamin D and calcitriol could favourably influence immunity have been reported in the past 30 years: it has been shown that vitamin D (through calcitriol) reduces differentiation of monocytes to DCs and differentiation and proliferation of DCs, thus decreasing T-cell stimulation [Griffin et al 2001]; controls T-cell activation [von Essen et al 2010] and inhibits T-cell proliferation [Rigby et al 1990;Lemire et al 1984]; reduces the production of interleukin (IL)-2 (growth factor for T cells) [Müller et al 1993]; suppresses in vitro and in vivo production of proinflammatory Th1 cell-derived IFNγ and tumour necrosis factor α [Reichel et al 1987;Lemire et al 1995;Baeke et al 2010;Zhang et al 2012]; reduces proinflammatory Th17 activity and IL-17 production [Tang et al 2009;Ikeda et al 2010;Bruce et al 2011;Joshi et al 2011;Allen et al 2012]; enhances the production of the antiinflammatory cytokine IL-10 [ Heine et al 2008;Baeke et al 2010;Allen et al 2012]; promotes in vitro and in vivo the development of Tregs expressing cytotoxic T lymphocyte antigen 4 and forkhead box P3, resulting in an anti-inflammatory effect [Jeffery et al 2009;Prietl et al 2010;Khoo et al 2012;Urry et al 2012]; enhances the transformation of CD4 T lymphocytes into a Th2 phenotype (with a protective role) [Boonstra et al 2001;…”