title: Cell type-specific regulatory effects of glucocorticoids on cutaneous TLR2 expression and signalling.
abstract: Glucocorticoids (GCs) induce Toll-like receptor (TLR) 2 expression and synergistically upregulate TLR2 with pro-inflammatory cytokines or bacteria. These paradoxical effects have drawn attention to the inflammatory initiating or promoting effects of GCs, as GC treatment can provoke inflammatory skin diseases. Here, we aimed to investigate the regulatory effects of GCs in human skin cells of different epidermal and dermal layers. We found that Dex induced TLR2 expression mainly in undifferentiated and less in calcium-induced differentiated keratinocytes but not in HaCaT cells or fibroblasts, however, Dex reduced TLR1/6 expression. Stimulation with Dex under inflammatory conditions further increased TLR2 but not TLR1 or TLR6 levels in keratinocytes. Increased ligand-induced interaction of TLR2 with MyD88 and expression of the adaptor protein TRAF6 indicated enhanced TLR2 signalling, whereas TLR2/1 or TLR2/6 signalling was not increased in Dex-pretreated keratinocytes. GC-increased TLR2 expression was negatively regulated by JNK MAPK signalling when stimulated with Propionibacterium acnes. Our results provide novel insights into the molecular mechanisms of glucocorticoid-mediated expression and function of TLR2 in human skin cells and the understanding of the mechanisms of corticosteroid side effects.
authors.affiliation: Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Berlin, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Su
authors.affiliation: Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Pfalzgraff
authors.affiliation: Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Berlin, Germany. Electronic address: Guenther.Weindl@fu-berlin.de.
authors.forename: Günther
authors.initials: G
authors.lastname: Weindl
mesh_terms: D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003907:Dexamethasone / Q000009:adverse effects*; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D016209:Interleukin-8 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011425:Propionibacterium acnes / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; D005938:Glucocorticoids; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D003907:Dexamethasone
keywords: Dexamethasone; Glucocorticoids; Inflammation; Skin; Toll-like receptors