DIFFERENTIAL MODULATION OF IL-1-INDUCED ENDOTHELIAL ADHESION MOLECULES AND TRANSENDOTHELIAL MIGRATION OF GRANULOCYTES BY G-CSF

Granulocyte colony stimulating factor (G-CSF) is widely used for mobil ization of haemopoietic stem cells into the peripheral blood. However, little is known about the mechanisms involved in mobilization and the immune modulatory effects of this growth factor. In this report we sh ow that G-CSF down-regulated intercellular adhesion molecule 1 (ICAM-1 ) induced by Interleukin-1 (IL-1) on human endothelial cells. Interest ingly, the G-CSF-mediated down-modulation of IL-1-induced ICAM-1 appea red to be biphasic. In pharmacological concentrations (>300 ng/ml), an d in dose ranges of plasma G-CSF levels above that of nonfebrile healt hy individuals (30 pg/ml), a significant decrease in surface ICAM-1 co uld be observed. This could be explained, at least in part, by an incr eased autocrine G-CSF production by endothelial cells in response to I L-1 and exogenous G-CSF. In contrast to ICAM-1, IL-1-triggered VCAM-1 expression was superinduced by G-CSF with the optimal concentration of 30 pg/ml. To evaluate the functional significance of these findings, Cr-51 adhesion assays with peripheral blood mononuclear cells (PBMC) o r granulocytes known to lack the VCAM-1 counter-receptor very late ant igen 4 (VLA-4) and IL-1-stimulated endothelial cells, in the presence or absence of G-CSF were performed. G-CSF could not inhibit the IL-1-i nduced adhesion of PBMC to endothelial cells, which may be due to the differential adhesion molecule modulation. In contrast, granulocyte ad hesion induced by IL-1 could effectively be blocked by co-incubation w ith G-CSF. Finally, G-CSF also inhibited transendothelial migration of granulocytes through IL-1-activated endothelial cells in a concentrat ion-dependent manner.