title: Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses.
abstract: Sphingosine 1-phosphate (S1P) levels in cells and, consequently, its bioactivity as a signalling molecule are controlled by the action of enzymes responsible for its synthesis and degradation. In the present report, we examined alterations in expression patterns of enzymes involved in S1P-metabolism (sphingosine kinases including their splice variants, sphingosine 1-phosphate phosphatases, and sphingosine 1-phosphate lyase) under certain inflammatory conditions. We found that sphingosine kinase type 1 (SPHK1) mRNA could be triggered in a cell type-specific manner; individual SPHK1 splice variants were induced with similar kinetics. Remarkably, expression and activity of S1P phosphatase 2 (SPP2) was found to be highly upregulated by inflammatory stimuli in a variety of cells (e.g., neutrophils, endothelial cells). Bandshift analysis using oligonucleotides spanning predicted NFkappaB sites within the SPP2 promoter and silencing of NFkappaB/RelA via RelA-directed siRNA demonstrated that SPP2 is an NFkappaB-dependent gene. Silencing of SPP2 expression in endothelial cells, in turn, led to a marked reduction of TNF-alpha-induced IL-1beta mRNA and protein and to a partial reduction of induced IL-8, suggesting a pro-inflammatory role of SPP2. Notably, up-regulation of SPP2 was detected in samples of lesional skin of patients with psoriasis, an inflammatory skin disease. This study provides detailed insights into the regulation of SPP2 gene expression and suggests that SPP2 might be a novel player in pro-inflammatory signalling.
authors.affiliation: Novartis Institutes for BioMedical Research, Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. diana.mechtcheriakova@novartis.com
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Alexander
authors.initials: A
authors.lastname: Wlachos
authors.forename: Jury
authors.initials: J
authors.lastname: Sobanov
authors.forename: Tamara
authors.initials: T
authors.lastname: Kopp
authors.forename: Roland
authors.initials: R
authors.lastname: Reuschel
authors.forename: Frederic
authors.initials: F
authors.lastname: Bornancin
authors.forename: Richard
authors.initials: R
authors.lastname: Cai
authors.forename: Barbara
authors.initials: B
authors.lastname: Zemann
authors.forename: Nicole
authors.initials: N
authors.lastname: Urtz
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zlabinger
authors.forename: Maximilian
authors.initials: M
authors.lastname: Woisetschläger
authors.forename: Thomas
authors.initials: T
authors.lastname: Baumruker
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011565:Psoriasis / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000201:enzymology / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D008565:Membrane Proteins; D016328:NF-kappa B; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C498526:SGPP2 protein, human