Sphingosine 1-phosphate potentiates human lung fibroblast chemotaxis through the S1P2 receptor

Mitsu Hashimoto, Xingqi Wang, Lijun Mao, Tetsu Kobayashi, Shin Kawasaki, Naoyoshi Mori, Myron L. Toews, Jung Kim Hui, D. Roselyn Cerutis, Xiangde Liu, Stephen I. Rennard

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Migration of fibroblasts plays an essential role in tissue repair after injury. Sphingosine 1-phosphate (S1P) is a multifunctional mediator released by many cells that can be released in inflammation and after injury. This study evaluated the effect of S1P on fibroblast chemo-taxis toward fibronectin. S1P alone did not affect fibroblast migration, but S1P enhanced fibronectin-directed chemotaxis in a concentration-dependent manner. The effect of S1P was not mimicked by dihydro (dh) S1P or the S1P1 receptor agonist SEW2871. S1P augmentation of fibroblast chemotaxis, however, was completely blocked by JTE-013, an S1P2 antagonist, but not by suramin, an S1P3 antagonist. Suppression of the S1P2 receptor by small interfering (si)RNA also completely blocked S1P augmentation of fibroblast chemotaxis to fibronectin. S1P stimulated Rho activation and focal adhesion kinase (FAK) phosphorylation, and these were also significantly inhibited by the S1P 2 receptor antagonist (JTE-013) or by S1P2 siRNA. Further, the potentiation of S1P signaling was blocked by the Rho-kinase inhibitor Y-27632 in a concentration-dependent manner. Inhibition of FAK with siRNA reduced basal chemotaxis toward fibronectin slightly but significantly, and almost completely blocked S1P augmented chemotaxis. These results suggest that S1P-augmented fibroblast chemotaxis toward fibronectin depends on the S1P 2 receptor and requires Rho and Rho-kinase, and FAK phosphorylation. By augmenting fibroblast recruitment, S1P has the potential to modulate tissue repair after injury. The pathways by which S1P mediates this effect, therefore, represent a potential therapeutic target to affect tissue repair and remodeling.

Original languageEnglish (US)
Pages (from-to)356-363
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume39
Issue number3
DOIs
StatePublished - Sep 1 2008

Keywords

  • Fibroblasts
  • Fibronectin
  • Migration
  • Sphingosine 1-phosphate

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Hashimoto, M., Wang, X., Mao, L., Kobayashi, T., Kawasaki, S., Mori, N., Toews, M. L., Hui, J. K., Cerutis, D. R., Liu, X., & Rennard, S. I. (2008). Sphingosine 1-phosphate potentiates human lung fibroblast chemotaxis through the S1P2 receptor. American journal of respiratory cell and molecular biology, 39(3), 356-363. https://doi.org/10.1165/rcmb.2006-0427OC