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

研究成果: Contribution to journalArticle査読

21 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)4863-4872
ページ数10
ジャーナルJournal of Immunology
185
8
DOI
出版ステータス出版済み - 10 15 2010

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学

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