title: IL-27 Regulates IL-18 binding protein in skin resident cells.
abstract: IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48-72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts.
authors: Division of Rheumatic and Musculoskeletal Disease, Leeds Institute of Molecular Medicine, LMBRU LTHT, University of Leeds, Leeds, United Kingdom. M.Wittmann@leeds.ac.uk
authors: Miriam
authors: M
authors: Wittmann
authors: Rosella
authors: R
authors: Doble
authors: Malte
authors: M
authors: Bachmann
authors: Josef
authors: J
authors: Pfeilschifter
authors: Thomas
authors: T
authors: Werfel
authors: Heiko
authors: H
authors: Mühl
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D052816:Foreskin / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein; D018664:Interleukin-12; D007371:Interferon-gamma; D008156:Luciferases