title: IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway.
abstract: 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.
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, CA 90095, USA.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Robles
authors.forename: Steffen
authors.initials: S
authors.lastname: Stenger
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: 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
chemical_list: 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