IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway.
An essential function of the innate immune system is to directly trigger antimicrobial mechanisms to defend against invading pathogens. In humans, one such pathway involves activation by TLR2/1L leading to the vitamin D-dependent induction of antimicrobial peptides. In this study, we found that TLR2/1-induced IL-15 was required for induction of CYP27b1, the VDR and the downstream antimicrobial peptide cathelicidin. Although both IL-15 and IL-4 triggered macrophage differentiation, only IL-15 was sufficient by itself to induce CYP27b1 and subsequent bioconversion of 25-hydroxyvitamin D3 (25D3) into bioactive 1,25D3, leading to VDR activation and induction of cathelicidin. Finally, IL-15-differentiated macrophages could be triggered by 25D3 to induce an antimicrobial activity against intracellular Mycobacterium tuberculosis. Therefore, IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway.
Krutzik
Stephan R
SR
Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
Hewison
Martin
M
Liu
Philip T
PT
Robles
Juan Antonio
JA
Stenger
Steffen
S
Adams
John S
JS
Modlin
Robert L
RL
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000276:immunology / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000382:microbiology / Q000502:physiology; D018167:Receptors, Calcitriol / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051194:Toll-Like Receptor 1 / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D014807:Vitamin D / Q000276:immunology / Q000378:metabolism*; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D019409:Interleukin-15; D018167:Receptors, Calcitriol; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D054804:Cathelicidins