title: Vitamin d-directed rheostatic regulation of monocyte antibacterial responses.
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.
authors.affiliation: Orthopaedic Hospital Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, 90095, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.forename: Songyang
authors.initials: S
authors.lastname: Ren
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Rene F
authors.initials: RF
authors.lastname: Chun
authors.forename: Venu
authors.initials: V
authors.lastname: Lagishetty
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Gombart
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis / Q000276:immunology; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism; D054804:Cathelicidins; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051194:Toll-Like Receptor 1 / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D014808:Vitamin D Deficiency / Q000276:immunology* / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D012333:RNA, Messenger; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase