title: T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism.
abstract: We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D(3) (25D(3)) to its active metabolite 1,25D(3). In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D(3) to the inactive metabolite 24,25D(3), and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens.
authors.affiliation: Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Edfeldt
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Rene
authors.initials: R
authors.lastname: Chun
authors.forename: Mario
authors.initials: M
authors.lastname: Fabri
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheelwright
authors.forename: Caroline
authors.initials: C
authors.lastname: Keegan
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002117:Calcitriol / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; C106641:DEFB4A protein, human; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D023083:beta-Defensins; D014807:Vitamin D; D015847:Interleukin-4; D007371:Interferon-gamma; C104450:25-hydroxyvitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D054804:Cathelicidins