Vitamin d-directed rheostatic regulation of monocyte antibacterial responses

J Immunol. 2009 Apr 1;182(7):4289-95. doi: 10.4049/jimmunol.0803736.

Abstract

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)(2)D from precursor 25-hydroxyvitamin D(3) (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D(2) twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D "insufficient" conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p < 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p < 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p < 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / biosynthesis
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / immunology
  • Antimicrobial Cationic Peptides / immunology*
  • Antimicrobial Cationic Peptides / metabolism
  • Cathelicidins
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression
  • Humans
  • Immunity, Innate*
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 1 / immunology
  • Toll-Like Receptor 1 / metabolism
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Vitamin D / analogs & derivatives*
  • Vitamin D / immunology
  • Vitamin D / metabolism
  • Vitamin D / therapeutic use
  • Vitamin D Deficiency / immunology*
  • Vitamin D Deficiency / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • RNA, Messenger
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Vitamin D
  • ropocamptide
  • 1,25-dihydroxyvitamin D
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase