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Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells
- Source :
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1841:11-21
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1β (IL-1β). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P-dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases.
- Subjects :
- Male
medicine.medical_specialty
MAP Kinase Signaling System
medicine.medical_treatment
Interleukin-1beta
Sphingosine kinase
Biology
Dinoprostone
Gene Expression Regulation, Enzymologic
Rats, Sprague-Dawley
chemistry.chemical_compound
Sphingosine
Internal medicine
medicine
Animals
Humans
Vasoconstrictor Agents
Cyclooxygenase Inhibitors
Sphingosine-1-phosphate
610 Medicine & health
Sphingosine-1-Phosphate Receptors
Molecular Biology
Cells, Cultured
Mitogen-Activated Protein Kinase 1
Sulfonamides
Mitogen-Activated Protein Kinase 3
Mesangial cell
Angiotensin II
Cell migration
Cell Biology
Rats
Up-Regulation
Cell biology
Receptors, Lysosphingolipid
Cytokine
Endocrinology
chemistry
Celecoxib
Cyclooxygenase 2
Mesangial Cells
Pyrazoles
lipids (amino acids, peptides, and proteins)
Lysophospholipids
Signal transduction
Subjects
Details
- ISSN :
- 13881981
- Volume :
- 1841
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Accession number :
- edsair.doi.dedup.....24414425be88e499d8d262f14053fcd8