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© The Rockefeller University Press, 0022-1007/1998/6/2023/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 12, June 15, 1998 2023-2030

Articles

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

Sonja Lechleitner*, Jens Gille{ddagger}, 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 {ddagger} 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

Address correspondence to Peter Petzelbauer, Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-7764; Fax: 43-1-408-1928; E-mail: peter.petzelbauer{at}akh-wien.ac.at

Abbreviations used: ELAM, endothelial leukocyte adhesion molecule; HUVEC, human umbilical endothelial vein endothelial cells; IRF, interferon-related factor; NF, nuclear factor; VCAM, vascular cell adhesion molecule.


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