title: Novel sphingolipid derivatives promote keratinocyte differentiation.
abstract: Sphingolipids are important components of the water permeability barrier of the skin. Moreover, ceramides were also shown to influence keratinocyte differentiation and regulate cellular signalling. A confluence-induced differentiation model of normal human keratinocytes was established to allow evaluation of pro- and anti-differentiation effects of exogenous compounds. The effects of phytosphingosine (PS), sphingosine (SO), sphinganine (SA) and their hexanoyl (-C6), stearoyl (-C18) and salicyl (-SLC) derivatives, C12-alkylamine-salicylate (C12-SLC), salicylate (SLC) along with vitamin D3 (VD3) and retinol as control substances were tested in this system. Cytotoxicity assays were carried out to optimize the incubation conditions of compounds and whole genome expression changes were monitored by DNA-microarray on days 0, 1 and 4. Geometric means of gene expression levels of a subset of known keratinocyte differentiation-related genes were calculated from the microarray data to compare effects of the sphingolipid derivatives. Compound treatment-induced transcriptional changes were analysed by the ExPlain software (BIOBASE GmbH). Five of the assayed substances (SA, SO-C6, PS-C6, SO-SLC, PS-SLC) were found to be potent promoters of keratinocyte differentiation compared with VD3, and C12-SLC revealed potential anti-differentiation properties. ExPlain analysis found a different regulatory profile in the computed transcriptional networks of the sphingoid bases versus their -C6 and especially -SLC derivatives suggesting that the change in their keratinocyte differentiation modifying potential is due to a unique effect of the covalent attachment of the salicylic acid. Taken together, these results demonstrate the gene regulatory potential of sphingolipid species that could be valuable for dermatological or cosmetic applications.
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
authors.forename: György
authors.initials: G
authors.lastname: Paragh
authors.forename: Petra
authors.initials: P
authors.lastname: Schling
authors.forename: Peter
authors.initials: P
authors.lastname: Ugocsai
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Kel
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Susanne
authors.initials: S
authors.lastname: Heimerl
authors.forename: Christoph
authors.initials: C
authors.lastname: Moehle
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schiemann
authors.forename: Michael
authors.initials: M
authors.lastname: Wegmann
authors.forename: Mike
authors.initials: M
authors.lastname: Farwick
authors.forename: Norbert M
authors.initials: NM
authors.lastname: Wikonkál
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D000328:Adult; D000943:Antigens, Differentiation / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology; D005260:Female; D000091344:Filaggrin Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins / Q000235:genetics; D053550:Keratin-10 / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012459:Salicylates / Q000494:pharmacology; D013107:Sphingolipids / Q000494:pharmacology*; D011503:Transglutaminases / Q000235:genetics; D014801:Vitamin A / Q000494:pharmacology
chemical_list: D000943:Antigens, Differentiation; C109656:CDSN protein, human; D000091344:Filaggrin Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; C507493:KRT10 protein, human; D012459:Salicylates; D013107:Sphingolipids; D014801:Vitamin A; D053550:Keratin-10; D002762:Cholecalciferol; D011503:Transglutaminases; C105804:transglutaminase 1