Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.
Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Philip T
PT
Liu
Steffen
S
Stenger
Huiying
H
Li
Linda
L
Wenzel
Belinda H
BH
Tan
Stephan R
SR
Krutzik
Maria Teresa
MT
Ochoa
Jürgen
J
Schauber
Kent
K
Wu
Christoph
C
Meinken
Diane L
DL
Kamen
Manfred
M
Wagner
Robert
R
Bals
Andreas
A
Steinmeyer
Ulrich
U
Zügel
Richard L
RL
Gallo
David
D
Eisenberg
Martin
M
Hewison
Bruce W
BW
Hollis
John S
JS
Adams
Barry R
BR
Bloom
Robert L
RL
Modlin
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D001741:Black or African American; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002117:Calcitriol / Q000097:blood / Q000378:metabolism*; D054804:Cathelicidins; D015169:Colony Count, Microbial; D003713:Dendritic Cells / Q000382:microbiology / Q000502:physiology; D004198:Disease Susceptibility; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000502:physiology*; D009000:Monocytes / Q000382:microbiology / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D051193:Toll-Like Receptors / Q000502:physiology*; D014376:Tuberculosis / Q000209:etiology / Q000276:immunology; D015854:Up-Regulation; D065668:Vitamin D3 24-Hydroxylase
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D051193:Toll-Like Receptors; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol