Mevastatin ameliorates sphingosine 1-phosphate-induced COX-2/PGE2-dependent cell migration via FoxO1 and CREB phosphorylation and translocation

Chih Kai Hsu, Chih Chung Lin, Li Der Hsiao, Chuen Mao Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

24 Scopus citations

Abstract

Background and Purpose Sphingosine 1-phosphate (S1P), an important inflammatory mediator, has been shown to regulate COX-2 production and promote various cellular responses such as cell migration. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA), effectively inhibits inflammatory responses. However, the mechanisms underlying S1P-evoked COX-2-dependent cell migration, which is modulated by mevastatin in human tracheal smooth muscle cells (HTSMCs) remain unclear. Experimental Approach The expression of COX-2 was determined by Western blotting, real time-PCR and promoter analyses. The signalling molecules were investigated by pretreatment with respective pharmacological inhibitors or transfection with siRNAs. The interaction between COX-2 promoter and transcription factors was determined by chromatin immunoprecipitation assay. Finally, the effect of mevastatin on HTSMC migration and leukocyte counts in BAL fluid and COX-2 expression induced by S1P was determined by a cell migration assay, cell counting and Western blot. Key Results S1P stimulated mTOR activation through the Nox2/ROS and PI3K/Akt pathways, which can further stimulate FoxO1 phosphorylation and translocation to the cytosol. We also found that S1P induced CREB activation and translocation via an mTOR-independent signalling pathway. Finally, we showed that pretreatment with mevastatin markedly reduced S1P-induced cell migration and COX-2/PGE2 production via a PPARγ-dependent signalling pathway. Conclusions and Implications Mevastatin attenuates the S1P-induced increased expression of COX-2 and cell migration via the regulation of FoxO1 and CREB phosphorylation and translocation by PPARγ in HTSMCs. Mevastatin could be beneficial for prevention of airway inflammation in the future.

Original languageEnglish
Pages (from-to)5360-5376
Number of pages17
JournalBritish Journal of Pharmacology
Volume172
Issue number22
DOIs
StatePublished - 01 11 2015

Bibliographical note

Publisher Copyright:
© 2015 The British Pharmacological Society.

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