Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin‐4 selectively induces expression of vascular cell adhesion molecule‐1 and P‐selectin resulting in preferential adhesion of lymphocytes

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Abstract
Summary: The expression of adhesion molecules on vascular endothelial cells determines the pattern of migration and extravasation of leucocytes in inflammation and immunity. Here we show that costimulation with CD40 ligand (CD40L) and interleukin (IL)‐4 (or IL‐13) gives rise to a unique pattern of adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). CD40 ligation alone enhanced expression of vascular cell adhesion molecule‐1 (VCAM‐1), intracellular adhesion molecule‐1 (ICAM‐1) and E‐selectin whereas IL‐4 and IL‐13 increased expression of VCAM‐1 and P‐selectin but not ICAM‐1 or E‐selectin. When IL‐4 and CD40L were combined there was an additional increase of both VCAM‐1 and P‐selectin, but ICAM‐1 and E‐selectin were both inhibited. The combined effects of IL‐4 and CD40L signalling were not the result of altered response kinetics, enhanced sensitivity of the endothelium, or increased expression of CD40 or the IL‐4 receptor. The rise in VCAM‐1 expression induced by combined IL‐4 and CD40L stimulation was slower and more sustained than with tumour necrosis factor‐α (TNF‐α) and occurred only on a subset (75–80%) of the endothelial cell population compared to 100% with TNF‐α. Costimulation with IL‐4 and CD40L increased adhesion of T cells and B cells above levels obtained with either signal alone, but decreased adhesion of neutrophils. Furthermore, CD40 and IL‐4 synergistically increased IL‐6 but decreased IL‐8 production by HUVEC. These results show that interactions between IL‐4 and CD40 on endothelial cells give rise to specific patterns of adhesion molecule expression and cytokine production that may have important implications for lymphocyte and neutrophil migration and function at sites of inflammation.