Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1

J Immunol. 2012 Mar 1;188(5):2127-35. doi: 10.4049/jimmunol.1102412. Epub 2012 Feb 1.


It is estimated that 1 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 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)(2)D(3), and 25(OH)D(3), 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 MAPK 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 with 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / immunology
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / biosynthesis
  • Drug Delivery Systems* / methods
  • Dual Specificity Phosphatase 1 / deficiency
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism*
  • Humans
  • Inflammation Mediators / antagonists & inhibitors*
  • Inflammation Mediators / metabolism
  • L Cells
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology*
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / immunology*
  • Monocytes / pathology
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Vitamin D / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • Vitamin D
  • p38 Mitogen-Activated Protein Kinases
  • Dual Specificity Phosphatase 1