title: Regulation of the extrarenal CYP27B1-hydroxylase.
abstract: Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-β, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States; Department of Molecular, Cell and Developmental Biology, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States; Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095-7322, United States. Electronic address: jsadams@mednet.ucla.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States. Electronic address: brafison@mednet.ucla.edu.
authors.forename: Brandon
authors.initials: B
authors.lastname: Rafison
authors.affiliation: Clinical and Translational Research Center, Center for the Health Sciences, David Geffen School of Medicine, 10833 Le Conte Avenue, BE-144, Los Angeles, CA 90095, United States. Electronic address: switzel@mednet.ucla.edu.
authors.forename: Sten
authors.initials: S
authors.lastname: Witzel
authors.affiliation: Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095-7322, United States. Electronic address: rereyes@mednet.ucla.edu.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Reyes
authors.affiliation: Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095-7322, United States. Electronic address: ashieh@mednet.ucla.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: Shieh
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States. Electronic address: rchun@mednet.ucla.edu.
authors.forename: Rene
authors.initials: R
authors.lastname: Chun
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States. Electronic address: kathryn.zavala@gmail.com.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Zavala
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States; Department of Molecular, Cell and Developmental Biology, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States. Electronic address: mhewison@mednet.ucla.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. South, Ste. 410, Los Angeles, CA 90095-7358, United States; Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095-7322, United States. Electronic address: ptliu@mednet.ucla.edu.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000201:enzymology*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014158:Transcription, Genetic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: Hydroxylase; Immunology; Innate immunity; Intracrine; Macrophage; Vitamin D