Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1.
Open Access
- 1 July 1996
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 184 (1), 173-182
- https://doi.org/10.1084/jem.184.1.173
Abstract
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.Keywords
This publication has 67 references indexed in Scilit:
- Synergistic activation of intercellular adhesion molecule 1 (ICAM‐1) by TNF‐α and IFN‐γ is mediated by p65/p50 and p65/c‐Rel and interferon‐responsive factor Statlα (p91) that can be activated by both IFN‐γ and IFN‐αFEBS Letters, 1994
- Structural characteristics of CD40 ligand that determine biological functionSeminars in Immunology, 1994
- Interferon-alpha and interleukin 2 synergistically enhance basic fibroblast growth factor synthesis and induce release, promoting endothelial cell growth.JCI Insight, 1993
- Endothelial-Leukocyte Adhesion MoleculesAnnual Review of Immunology, 1993
- Molecular and biological characterization of a murine ligand for CD40Nature, 1992
- Endothelial Expression of a Mononuclear Leukocyte Adhesion Molecule During AtherogenesisScience, 1991
- Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration.JCI Insight, 1988
- Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferaseGene, 1988
- Histological features of skin reactions to human lymphoid cell line lymphokine in patients with advanced cancerThe Journal of Pathology, 1982
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970