Sphingosine-1-phosphate mediates COX-2 expression and PGE2/IL-6 secretion via c-Src-Dependent AP-1 activation

Chih Kai Hsu, I-Ta Lee, Chih Chung Lin, Li Der Hsiao, Chuen Mao Yang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)702-715
Number of pages14
JournalJournal of Cellular Physiology
Volume230
Issue number3
DOIs
Publication statusPublished - Mar 1 2015
Externally publishedYes

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Transcription Factor AP-1
Cyclooxygenase 2
Dinoprostone
Interleukin-6
Chemical activation
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Phosphorylation
Celecoxib
Proto-Oncogene Proteins c-jun
sphingosine 1-phosphate
Proto-Oncogene Proteins c-fos
Pulmonary diseases
Messenger RNA
Cyclooxygenase 2 Inhibitors
Small Interfering RNA
Smooth Muscle Myocytes
Transfection
Muscle

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Sphingosine-1-phosphate mediates COX-2 expression and PGE2/IL-6 secretion via c-Src-Dependent AP-1 activation. / Hsu, Chih Kai; Lee, I-Ta; Lin, Chih Chung; Hsiao, Li Der; Yang, Chuen Mao.

In: Journal of Cellular Physiology, Vol. 230, No. 3, 01.03.2015, p. 702-715.

Research output: Contribution to journalArticle

Hsu, Chih Kai ; Lee, I-Ta ; Lin, Chih Chung ; Hsiao, Li Der ; Yang, Chuen Mao. / Sphingosine-1-phosphate mediates COX-2 expression and PGE2/IL-6 secretion via c-Src-Dependent AP-1 activation. In: Journal of Cellular Physiology. 2015 ; Vol. 230, No. 3. pp. 702-715.
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