We have reported previously that activation of human umbilical vein endothelial cells (HUVECs) through CD40, using a recombinant soluble form of trimerized CD40 ligand, leads to induction of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Here, we compare the effects of CD40 ligand with those of tumor necrosis factor (TNF) and interleukin 1 (IL-1). All three ligands induce transient increases in E-selectin (peak 4 h) and VCAM-1 (peak 8-24 h), as well as sustained increases in ICAM-1 (plateau 24 h). Quantitatively, TNF is more potent than IL-1, which is much more potent than CD40 ligand. The same hierarchy is observed for transcriptional activation of an E-selectin promoter reporter gene construct in transiently transfected HUVECs. TNF and CD40 ligand each induced activation of the transcription factors NF-kappa B, IRF-1, and ATF-2/c-Jun, measured by electrophoretic mobility shift assays, but this response appeared quantitatively similar. All three agents transiently (peak 30 min) activated Jun NH2-terminal kinase (JNK), which has been implicated in transcription of E-selectin through its actions on ATF-2/c-Jun. Activation of JNK again showed a hierarchy of potency (TNF > IL-1 > CD40 ligand), although the time course of induction was similar for all three agents. After 44 h of pretreatment, TNF, IL-1, and CD40 ligand each display homologous desensitization for reinduction of surface expression of E-selectin. A similar pattern of homologous desensitization for reactivation of JNK was observed. We conclude that TNF, IL-1, and CD40 ligand all activate similar responses in ECs, and that homologous desensitization of JNK may explain the inability of individual cytokines to reinduce E-selectin expression.
Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1.
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K Karmann, W Min, W C Fanslow, J S Pober; Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1.. J Exp Med 1 July 1996; 184 (1): 173–182. doi: https://doi.org/10.1084/jem.184.1.173
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