Dihydrosphingosine 1-phosphate stimulates MMP1 gene expression via activation of ERK1/2-Ets1 pathway in human fibroblasts.
Sphingosine kinase (SphK) is a conserved lipid kinase that catalyzes formation of important regulators of inter- and intracellular signaling, sphingosine-1 phosphate (S1P), and dihydrosphingosine 1-phosphate (dhS1P). In this study, we investigated the role of SphK1 in the regulation of expression of matrix metalloproteinase 1 (MMP1) in dermal fibroblasts, a key event in regulation of extra cellular matrix. We show that overexpression of SphK1 up-regulated MMP1 protein, MMP1 mRNA, and MMP1 promoter activity, and this action of SphK1 required activation of the ERK1/2-Ets1 and NF-kappaB pathways. Furthermore, experiments using SphK1 specific siRNA demonstrated that SphK1 is required for the TNF-alpha stimulation of MMP1. Additional data revealed a specific role of dhS1P, and not S1P, as a mediator of SphK1-dependent activation of ERK1/2 and up-regulation of MMP1. The stimulatory effect of dhS1P was sensitive to pertussis toxin, suggesting a possible involvement of a G-protein-coupled receptor. In contrast, S1P, but not dhS1P, stimulated the induction of COX-2, which demonstrated selective actions of these two closely related bioactive lipids. In conclusion, this study describes a novel mode of SphK1 signaling through generation of dhS1P with a key role in mediating transcriptional responses to TNF-alpha. This is the first report of selective function of dhS1P as compared with the better studied S1P.
Bu
Shizhong
S
Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Yamanaka
Masayoshi
M
Pei
Huiping
H
Bielawska
Alicja
A
Bielawski
Jacek
J
Hannun
Yusuf A
YA
Obeid
Lina
L
Trojanowska
Maria
M
D002518:Ceramides; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B; D037342:Pertussis Toxin; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation; D000099157:Sphingosine Kinase
D002518:Ceramides; D048049:Extracellular Signal-Regulated MAP Kinases; D008246:Lysophospholipids; D020781:Matrix Metalloproteinase 1; D016328:NF-kappa B; D037342:Pertussis Toxin; D017853:Phosphotransferases (Alcohol Group Acceptor); D050784:Proto-Oncogene Protein c-ets-1; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C494041:ETS1 protein, human; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate