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Sphingosine-1-Phosphate Mediates COX-2 Expression and PGE2/IL-6 Secretion via c-Src-Dependent AP-1 Activation
- Source :
- Journal of Cellular Physiology. 230:702-715
- Publication Year :
- 2014
- Publisher :
- Wiley, 2014.
-
Abstract
- Sphingosine-1-phosphate (S1P) has been shown to regulate cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2 ) expression and IL-6 secretion in various respiratory diseases. However, the mechanisms underlying S1P-induced COX-2 expression and PGE2 production in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here we demonstrated that S1P markedly induced COX-2 expression. S1P also induced PGE2 and IL-6 secretion which were reduced by the inhibitors of COX-2 (NS-398 and celecoxib). Pretreatment with the inhibitor of S1PR1 (W123), S1PR3 (CAY10444), c-Src (PP1), PYK2 (PF431396), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of S1PR1, S1PR3, c-Src, PYK2, p38, p42, JNK2, c-Jun, or c-Fos reduced S1P-induced COX-2 expression and PGE2 /IL-6 secretion. Moreover, S1P induced c-Src, PYK2, p42/p44 MAPK, JNK1/2, p38 MAPK, and c-Jun phosphorylation. We observed that S1P-induced p42/p44 MAPK and JNK1/2, but not p38 MAPK activation was mediated via a c-Src/PYK2-dependent pathway. S1P also enhanced c-Fos, but not c-Jun mRNA and protein expression and the AP-1 promoter activity. S1P-induced c-Fos mRNA and protein expression, c-Jun phosphorylation, and AP-1 promoter activity was reduced by W123, CAY10444, PP1, PF431396, U0126, SP600125, or SB202190. These results demonstrated that S1P-induced COX-2 expression and PGE2 /IL-6 generation was mediated through S1PR1/3/c-Src/PYK2/p42/p44 MAPK- or JNK1/2- and S1PR1/3/c-Src/p38 MAPK-dependent AP-1 activation.
- Subjects :
- MAPK/ERK pathway
endocrine system
Physiology
p38 mitogen-activated protein kinases
Clinical Biochemistry
Cell Biology
Transfection
Biology
environment and public health
Molecular biology
Cell biology
enzymes and coenzymes (carbohydrates)
chemistry.chemical_compound
chemistry
Phosphorylation
lipids (amino acids, peptides, and proteins)
Secretion
Sphingosine-1-phosphate
biological phenomena, cell phenomena, and immunity
S1PR1
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 00219541
- Volume :
- 230
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi...........615e93dcd001edb3e2411ce96b334b26