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Sphingosine 1-Phosphate Potentiates Human Lung Fibroblast Chemotaxis through the S1P₂ Receptor

¹ Pulmonary, Critical Care and Sleep Medicine, and ³ Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska; ² Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan; ⁴ Won Kwang University, Kunpo Medical Center, Seoul, Republic of Korea; and ⁵ School of Dentistry, Creighton University Medical Center, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu

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 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 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 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 after injury. The pathways by which S1P mediates this effect, therefore, represent a potential therapeutic target to affect tissue repair and remodeling.

Key Words: sphingosine 1-phosphate • fibroblasts • migration • fibronectin

CLINICAL RELEVANCE Sphingosine 1-phosphate could be one possible therapeutic target for fibrosis.