Gastrin induces the interaction between human mononuclear leukocytes and endothelial cells through the endothelial expression of P-selectin and VCAM-1

Gastric mucosal inflammation is frequently associated with hypergastrinemia, and a correlation exists between the level of gastrin and degree of gastritis. We have previously observed that gastrin promotes leukocyte-endothelial interactions and contributes to Helicobacter -induced inflammation in the rat mesentery. In the present study, we aimed to evaluate a possible proinflammatory activity of gastrin in humans. The interaction between human leukocytes [U-937 cells, peripheral blood polymorphonuclear (PMN), and peripheral blood mononuclear (PBMC) cells] and human umbilical vein endothelial cells (HUVEC) was analyzed in static and dynamic conditions. The endothelial expression of adhesion molecules [P-selectin, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule (VCAM)-1] was analyzed by flow cytometry and fluorescent microscopy screening. Gastrin increased the static adhesion of U-937 cells to HUVEC (1 h; 10−9M: 122 ± 9%; 10−8M: 143 ± 17%; 10−7M: 162 ± 14% vs. control, all P < 0.05). Incubation of HUVEC with gastrin (4 h) also increased PBMC rolling (vehicle: 63 ± 12; 10−9M: 109 ± 29; 10−8M: 141 ± 24; 10−7M: 261 ± 16 leukocytes/min, P < 0.05) and adhesion (vehicle: 3 ± 2, 10−9M: 11 ± 4, 10−8M: 17 ± 5, 10−7M: 15 ± 5 leukocytes/mm2, all P < 0.05) in the parallel-plate flow chamber. Treatment of PBMC with gastrin had no effects. The cholecystokinin (CCK)-2 receptor antagonist (L-365,260, 10−7M) prevented the effects of gastrin. P-selectin and VCAM-1 expression were enhanced by gastrin, and neutralizing antibodies against these molecules prevented PBMC rolling and adhesion. Gastrin did not affect the interactions between HUVEC and PMN. Gastrin induces interactions between human mononuclear leukocytes and endothelial cells through the activation of CCK-2 receptors and the enhancement of endothelial P-selectin and VCAM-1.