Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 33, Pages 30227-30235Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111078200
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- NHLBI NIH HHS [HL47671, HL71152] Funding Source: Medline
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Sphingosine 1-phosphate (S1P), a potent bioactive sphingolipid, has been implicated in many critical cellular events, including a regulatory role in the pathogenesis of airway inflammation. We investigated the participation of SIP as an inflammatory mediator by assessing interleukin-8 (IL-8) secretion and phospholipase D (PLD) activation in human bronchial epithelial cells (Bear-2B). S1P(1), S1P(3), S1P(4), S1P(5), and weak S1P(2) receptors were detected in Beas-2B and primary human bronchial epithelial cells. S1P stimulated a rapid activation of PLD, which was nearly abolished by pertussis toxin (PTX) treatment, consistent with S1P receptor/G(i) protein coupling. S1P also markedly induced Beas-2B secretion of IL-8, a powerful neutrophil chemoattractant and activator, in a PTX-sensitive manner. This S1P-mediated response was dependent on transcription as indicated by a strong induction of IL-8 promoter-mediated luciferase activity in transfected Beas-2B cells and a complete inhibition by actinomycin D. Beas-2B exposure to 1-butanol, which converts the PLD-generated phosphatidic acid (PA) to phosphatidylbutanol by a transphosphatidylation reaction, significantly attenuated the SIP-induced IL-8 secretion, indicating the involvement of PLD-derived PA in the signaling pathway. Inhibition of 12-O-tetradecanoyl-phorbol-13-acetate-stimulated IL-8 production by 1-butanol further strengthened this observation. Blocking protein kinase C and Rho kinase also attenuated SIP-induced IL-8 secretion. Our data suggest that PLD-derived PA, protein kinase C, and Rho are important signaling components in SIP-mediated IL-8 secretion by human bronchial epithelial cells.
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