Lysophosphatidic Acid Inhibits CC Chemokine Ligand 5/RANTES Production by Blocking IRF-1–Mediated Gene Transcription in Human Bronchial Epithelial Cells
Open Access
- 15 October 2010
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 185 (8), 4863-4872
- https://doi.org/10.4049/jimmunol.1000904
Abstract
Lysophosphatidic acid (LPA) is a phospholipid mediator that exerts a variety of biological responses through specific G-protein–coupled receptors (LPA1–LPA5 and P2Y5). LPA is thought to be involved in airway inflammation by regulating the expression of anti-inflammatory and proinflammatory genes. Chemokines such as CCL5/RANTES are secreted from airway epithelium and play a key role in allergic airway inflammation. CCL5/RANTES is a chemoattractant for eosinophils, T lymphocytes, and monocytes and seems to exacerbate asthma. We stimulated CCL5/RANTES production in a human bronchial epithelial cell line, BEAS-2B, with IFN-γ and TNF-α. When LPA was added, CCL5/RANTES mRNA expression and protein secretion were inhibited, despite the presence of IFN-γ and TNF-α. The LPA effect was attenuated by Ki16425, a LPA1/LPA3 antagonist, but not by dioctylglycerol pyrophosphate 8:0, an LPA3 antagonist. Pertussis toxin, the inhibitors for PI3K and Akt also attenuated the inhibitory effect of LPA on CCL5/RANTES secretion. We also identify the transcription factor IFN regulatory factor-1 (IRF-1) as being essential for CCL5/RANTES production. Interestingly, LPA inhibited IFN-γ and TNF-α–induced IRF-1 activation by blocking the binding of IRF-1 to its DNA consensus sequence without changing IRF-1 induction and its nuclear translocation. Ki16425, pertussis toxin, and PI3K inhibitors attenuated the inhibitory effect of LPA on IRF-1 activation. Our results suggest that LPA inhibits IFN-γ– and TNF-α–induced CCL5/RANTES production in BEAS-2B cells by blocking the binding of IRF-1 to the CCL5/RANTES promoter. LPA1 coupled to Gi and activation of PI3K is required for this unique effect.Keywords
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