MAST-CELLS ARE POTENT REGULATORS OF ENDOTHELIAL-CELL ADHESION MOLECULE ICAM-1 AND VCAM-1 EXPRESSION

To investigate the possible role of mast cells (MC) in regulating leuk ocyte adhesion to vascular endothelial cells (EC), microvascular and m acrovascular EC were exposed to activated MC or MC conditioned medium (MCCM). Expression of intercellular and vascular adhesion molecules (I CAM-1 and VCAM-1) on EC was monitored. incubation of human dermal micr ovascular endothelial cells (HDMEC) and human umbilical vein endotheli al cells (HUVEC) with activated MC or MCCM markedly increased ICAM-1 a nd VCAM-1 surface expression, noted as early as 4 hr. Maximal levels w ere observed at 16 hr followed by a general decline over 48 hr. A dose -dependent response was noted using incremental dilutions of MCCM or b y varying the number of MC in coculture with EC. At a ratio as low as 1:1,000 of MC:EC, increased ICAM-1 was observed. The ICAM-1 upregulati on by MCCM was >90% neutralized by antibody to tumor necrosis factor a lpha (TNF-alpha), suggesting that MC release of this cytokine contribu tes significantly to inducing EC adhesiveness. VCAM-1 expression enhan ced by MCCM was partly neutralized (70%) by anti body to TNF-alpha; th us other substances released by MC may contribute to VCAM-1 expression . Northern blot analysis demonstrated MCCM upregulated ICAM-1 and VCAM -1 mRNA in both HDMEC and HUVEC. To evaluate the function of MCCM-enha nced EC adhesion molecules, T cells isolated from normal human donors were used in a cell adhesion assay. T-cell binding to EC was increased significantly after exposure of EC to MCCM, and inhibited by antibodi es to ICAM-1 or VCAM-1. Intradermal injection of allergen in human ato pic volunteers known to develop late-phase allergic reactions led to m arked expression of both ICAM-1 and VCAM-1 at 6 hr, as demonstrated by immunohistochemistry. These studies indicate that MC play a critical role in regulating the expression of EC adhesion molecules, ICAM-1 and VCAM-1, and thus augment inflammatory responses by upregulating leuko cyte binding. (C) 1995 Wiley-Liss, Inc.