Sphingosine-1-phosphate induces thrombin receptor PAR-4 expression to enhance cell migration and COX-2 formation in human monocytes. Issue 4 (2nd July 2014)

• Record Type: Journal Article
• Authors: Mahajan-Thakur, Shailaja; Sostmann, Björn D; Fender, Anke C; Behrendt, Daniel; Felix, Stephan B; Schrör, Karsten; Rauch, Bernhard H
• Is Part Of: Journal of leukocyte biology. Volume 96:Issue 4(2014)
• Page Start: 611
• Page End: 618
• Publication Date: 2014-07-02
• Subjects: protease-activated receptors -- monocytes -- cyclooxygenase-2; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.3AB1013-567R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : S1P induces expression of the protease-activated receptor-4 (PAR-4) in human monocytes, and enhances chemotaxis and COX-2 formation in response to thrombin. Abstract: Thrombin is not only a central factor in blood coagulation but also stimulates inflammatory processes, including monocyte responses, via activation of PARs. The signaling lipid S1P is a major determinant of monocyte function. Here, we established an interaction between S1P and human monocyte responses to thrombin. S1P induced PAR-1 and PAR-4 mRNA and total protein expression in human monocytes and U937 cells in a concentration (0.1–10 μM)- and time (1–24 h)-dependent manner, respectively. However, only PAR-4 cell-surface expression was increased significantly by S1P, whereas PAR-1 remained unaffected. This response was associated with activation of the Akt, Erk, and p38 pathway and induction of COX-2 but not COX-1. PAR-4-mediated induction of COX-2 was prevented by the PI3K inhibitor LY (10 μM). Preincubation of human monocytes with S1P (1 μM; 16 h) resulted in an enhanced chemotaxis toward thrombin or to selective AP for PAR-4 but not PAR-1. Furthermore, down-regulation of PAR-4 transcription with siRNA attenuated the chemotactic response to thrombin and AP4. In conclusion, S1P enhances monocyte responses to thrombin via up-regulation of PAR-4 expression, which promotes cell migration and COX-2 abundance. This mechanism may facilitate monocyte recruitment to sites of vessel injury and inflammation.