Lysophosphatidic acid inhibits CC chemokine ligand 5/RANTES production by blocking IRF-1-mediated gene transcription in human bronchial epithelial cells

Shinichi Matsuzaki, Tamotsu Ishizuka, Takeshi Hisada, Haruka Aoki, Mayumi Komachi, Isao Ichimonji, Mitsuyoshi Utsugi, Akihiro Ono, Yasuhiko Koga, Kunio Dobashi, Hitoshi Kurose, Hideaki Tomura, Masatomo Mori, Fumikazu Okajima

Research output: Contribution to journalArticle

20 Citations (Scopus)

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-g and TNF-a. When LPA was added, CCL5/RANTES mRNA expression and protein secretion were inhibited, despite the presence of IFN-g and TNF-a. 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-g and TNF-a-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-g-and TNF-a-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.

Original languageEnglish
Pages (from-to)4863-4872
Number of pages10
JournalJournal of Immunology
Volume185
Issue number8
DOIs
Publication statusPublished - Oct 15 2010

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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