The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment

• Published in: Blood Vol. 98; no. 3; pp. 667 - 673
• Main Authors: Marin, Valérie, Farnarier, Catherine, Grès, Sandra, Kaplanski, Solange, Su, Michael S.-S., Dinarello, Charles A., Kaplanski, Gilles
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.08.2001; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Cells, Cultured; Chemokine CCL2 - biosynthesis; Chemokines - biosynthesis; Chemotaxis, Leukocyte - drug effects; Dose-Response Relationship, Drug; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Inflammation; Inflammation - metabolism; Interleukin-8 - biosynthesis; Kinetics; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Molecular and cellular biology; p38 Mitogen-Activated Protein Kinases; Phosphorylation - drug effects; Signal Transduction - drug effects; Thrombin - pharmacology; Umbilical Veins - cytology; Human; Blood coagulation; Cell culture; Endothelial cell; Serine endopeptidases; Pathophysiology; Enzyme; Leukocyte; Transferases; Cytokine; Thrombin; Inflammation; EC 2.7.1.37; Chemotaxis; Recruitment; Chemokine; Peptidases; Signal transduction; Protein kinase; Hydrolases; Coagulation factor; Umbilical vein; EC 3.4.21.5
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V98.3.667

Thrombin, the terminal serine protease in the coagulation cascade, is a proinflammatory molecule in vivo and induces endothelial activation in vitro. The cellular signaling mechanisms involved in this function are unknown. The role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in thrombin-induced chemokine production was studied. Phosphorylation of both p38 MAPK and its substrate, ATF-2, was observed in human umbilical vein endothelial cells (HUVECs) stimulated with thrombin, with a maximum after 5 minutes of stimulation. Using the selective p38 MAPK inhibitor SB203580, there was a significant decrease in thrombin-induced interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) protein production and messenger RNA steady-state levels. In addition, SB203580 decreased IL-8 and MCP-1 production induced by the thrombin receptor-1 agonist peptide (TRAP), suggesting functional links between the thrombin G protein–coupled receptor and the p38 MAPK pathway. Furthermore, endothelial activation in the presence of SB203580 decreased the chemotactic activity of thrombin-stimulated HUVEC supernatant on neutrophils and monocytic cells. In contrast, the p42/p44 MAPK pathway did not appear to be involved in thrombin- or TRAP-induced endothelial chemokine production, because there was no reduction in the presence of the p42/p44-specific inhibitor PD98059. These results demonstrate that the p38 rather than p42/44 MAPK signaling pathway plays an important role in thrombin-induced endothelial proinflammatory activation and suggest that inhibition of p38 MAPK may be an interesting target for anti-inflammatory strategies in vascular diseases combining thrombosis and inflammation.