Published ahead of print on March 26, 2008, doi:10.1165/rcmb.2006-0427OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 3, September 2008, 356-363 A more recent version of this article appeared on September 1, 2008
Submitted on November 16, 2006 Sphingosine 1-phosphate Potentiates Human Lung Fibroblast Chemotaxis through the S1P2 ReceptorMitsu Hashimoto1,1 Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan, 2 Department of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA, 3 Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE, USA, 4 Kunpo Medical Center, Won Kwang University, Seoul, Korea, Republic of, 5 Creighton University Medical Center, School of Denistry, Omaha, NE, USA * To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.
Migration of fibroblasts plays an essential role in tissue repair following injury. Sphingosine 1-phosphate (S1P) is a multifunctional mediator released by many cells that can be released in inflammation and following injury. This study evaluated the effect of S1P on fibroblast chemotaxis 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 siRNA 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 S1P2 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 S1P2 receptor and requires Rho and Rho-kinase, and FAK phosphorylation. By augmenting fibroblast recruitment, S1P has the potential to modulate tissue repair following injury. The pathways by which S1P mediates this effect, therefore, represent a potential therapeutic target to affect tissue repair and remodeling.
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