Abstract
The airway epithelium may release pro-inflammatory cytokines and chemokines in the asthmatic airway. Sphingosine 1-phosphate (S1P) is a bioactive lipid, increased in the airways of asthmatics, that may trigger the release of the potent neutrophil chemoattractant Interleukin-8 (IL-8) by epithelial cells. S1P is a ligand for 5 G protein-coupled receptors, S1PR1-5. We wished to explore the mechanisms of S1P induced IL-8 secretion with regard to the receptor(s) and downstream signaling events involved. Our results indicate that S1P induced IL-8 release is mediated by S1PR2 and the transcription factor NF-κB. Since the Epidermal Growth Factor Receptor (EGFR) and reactive oxygen species (ROS) have been implicated in IL-8 release in response to activation of other G protein-coupled receptors, we examined their importance in S1P induced IL-8 release and established that they are not involved. This study reveals S1PR2 and NF-κB as potential therapeutic targets in neutrophilic airway diseases such as severe asthma.
Highlights
Sphingosine 1phosphate (S1P) is a bioactive lipid important in immune system regulation, angiogenesis, migration and proliferation [1,2,3,4]
S1P INDUCES IL-8 Release To confirm that S1P induces IL-8 release from BEAS-2B cells, the cells were incubated with various concentrations of S1P for 4 hours
S1P Induced IL-8 Release is Mediated by S1PR2 To determine if S1P induced IL-8 release from airway epithelial cells is mediated by a specific S1P receptor, or group of receptors, BEAS-2B cells were pre-treated with specific S1P receptor inhibitors for 30 minutes prior to stimulation with S1P
Summary
S1P is a bioactive lipid important in immune system regulation, angiogenesis, migration and proliferation [1,2,3,4]. S1P is produced when sphingosine, derived from ceramide, is phosphorylated by sphingosine kinase I or II. There are currently five known S1P receptors (S1PR1-5) and these are G protein-coupled. S1P binding to these receptors can elicit diverse signaling mechanisms owing to the heterogeneity of these receptors and their coupling to different G proteins. S1P has been shown to be increased in the bronchoalveolar lavage of asthmatics upon segmental allergen challenge when compared to healthy control subjects [7]. S1P has been shown to induce contraction of airway smooth muscle cells, strengthening its potential role as an important lipid mediator in the asthmatic airway [8]
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