The Journal of Experimental Medicine
Cytokines Montreal 2008
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J. Exp. Med., Volume 187, Number 12, June 15, 1998 2023-2030

Interferon Enhances Tumor Necrosis Factor-induced Vascular Cell Adhesion Molecule 1 (CD106) Expression in Human Endothelial Cells by an Interferon-related Factor 1-dependent Pathway

By Sonja Lechleitner,* Jens Gille,Dagger David R. Johnson,§ and Peter Petzelbauer*

From the * Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, A-1090 Austria; the Dagger  Department of Dermatology, Goethe University, Frankfurt, Germany 60590; and the § Boyer Center of Molecular Biology,  Yale University, New Haven, Connecticut 06536

Tumor necrosis factor (TNF) and interleukin 1 are known to initiate endothelial vascular cell adhesion molecule (VCAM)-1 transcription primarily by activating nuclear factor (NF)-kappa B, which translocates to the nucleus. In addition to two NF-kappa B elements found within the minimal cytokine-inducible VCAM-1 promoter, an interferon-related factor (IRF) element (IRF-1) has been identified close to the transcription initiation site, suggesting that cytokines that induce IRF-1 might affect VCAM-1 expression levels. We therefore investigated the effects of interferons (IFNs), which strongly induce IRF-1, on VCAM-1 transcription and expression. We show that IFN-alpha and -gamma enhance TNF-induced VCAM-1 mRNA transcription and protein expression in human endothelial cells. IFN enhancement of TNF-induced expression is also seen using chloramphenicol acetyl transferase reporter genes linked to the minimal cytokine inducible VCAM-1 promoter. Nuclear IRF-1 is the molecular basis of IFN enhancement, because (a) IFN plus TNF-treated cells displayed increased nuclear IRF-1 levels and increased IRF-1 binding to the VCAM-1 promoter, compared with cells treated with TNF alone; (b) kinetics of nuclear IRF-1 levels correlated with VCAM-1 mRNA levels; (c) transfection with an IRF-1 construct substituted for IFN treatment; and (d) transfection with an expression construct encoding IRF-2, a competitive inhibitor of IRF-1, reduced TNF-induced VCAM-1 expression. Our experiments show that IFN amplifies TNF-induced VCAM-1 expression at the transcriptional level by an IRF-1-dependent pathway.

Key words: vascular cell adhesion molecule 1;  endothelium;  interferon;  interferon-related factor 1;  skin microvasculature


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