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.
Liu
Philip T
PT
Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Stenger
Steffen
S
Li
Huiying
H
Wenzel
Linda
L
Tan
Belinda H
BH
Krutzik
Stephan R
SR
Ochoa
Maria Teresa
MT
Schauber
Jürgen
J
Wu
Kent
K
Meinken
Christoph
C
Kamen
Diane L
DL
Wagner
Manfred
M
Bals
Robert
R
Steinmeyer
Andreas
A
Zügel
Ulrich
U
Gallo
Richard L
RL
Eisenberg
David
D
Hewison
Martin
M
Hollis
Bruce W
BW
Adams
John S
JS
Bloom
Barry R
BR
Modlin
Robert L
RL
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