Granulocyte colony-stimulating factor increases expression of adhesion receptors on endothelial cells through activation of p38 MAPK

Servicio de Hemoterapia-Hemostasia, Hospital Clinic, IDIBAPS, Barcelona, Spain.

BACKGROUND AND OBJECTIVES: Granulocyte colony-stimulating factor (G-CSF) is specific for the granulocytic cell line, although receptors for this cytokine have been found in other cell types including endothelial cells. These observations prompted us to investigate the potential effect of G-CSF on the endothelium. DESIGN AN METHODS: Endothelial cell monolayers were exposed to G-CSF to evaluate: i) signal transduction mechanisms, ii) expression of adhesion receptors at the cell surface, and iii) leukocyte adhesion on EC monolayers. RESULTS: Exposure of human umbilical vein endothelial cells (EC) in culture to G-CSF resulted in the activation of the signal transduction pathways JAK/STAT (JAK-1, STAT-1 and STAT-3) and RAS/MAPK (MAPK p42/44 and p38 MAPK). We also observed significantly increased expression of the adhesion receptors, E-selectin (ELAM-1), vascular endothelial cell adhesion molecule-1 and intracelleular adhesion molecule-1 at the cell surface in response to G-CSF, increases that were followed by an augmented adhesion of leukocytes on the previously exposed EC monolayers. These effects were blocked by the presence of SB203580, a p38 MAPK inhibitor, by U0126, a MAPK p42/44 inhibitor, and by inhibiting the G-CSF receptor with a specific antibody. INTERPRETATION AND CONCLUSIONS: Our results demonstrate that G-CSF increases the expression of adhesion receptors on EC, promoting leukocyte adhesion. This effect seems to be triggered by the signaling events that follow receptor binding. Results from experiments using specific inhibitors suggest that activation of p38 MAPK is required to promote expression of adhesion receptors in endothelial cells and the recruitment of leukocytes in response to G-CSF.