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Blood, 15 January 2002, Vol. 99, No. 2, pp. 520-525
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Cytokine-inducible CD40 expression in human endothelial cells is
mediated by interferon regulatory factor-1
Andreas H. Wagner,
Matthias Gebauer,
Beatrix Pollok-Kopp, and
Markus Hecker
From the Departments of Cardiovascular Physiology and
Immunology, University of Goettingen, Germany.
Given the significance of CD40-CD40 ligand interactions in chronic
inflammatory diseases including atherosclerosis, the transcriptional regulation of CD40 expression as a potential therapeutic target was
investigated in human umbilical vein cultured endothelial cells.
Exposure to interferon- (IFN-) plus tumor necrosis factor- resulted in a marked synergistic de novo expression of CD40, which, according to electrophoretic mobility shift analysis, was attributable to activation of the transcription factors nuclear factor- B
(NF-B), signal transducer and activator of transcription-1 (STAT-1),
and interferon regulatory factor-1 (IRF-1). Subsequent time-course studies revealed that de novo synthesis of IRF-1 preceded that of CD40.
Decoy oligodeoxynucleotide (ODN) neutralization of STAT-1 or IRF-1, but
not of NF-B, inhibited cytokine-stimulated CD40 expression by 60%
at both the mRNA and protein levels, and this effect was mimicked by
antisense ODN blockade of IRF-1 synthesis. In contrast, CD40 expression
in response to IFN- stimulation was sensitive to neutralization of
STAT-1 only. These findings suggest that depending on the cytokine
composition, CD40 expression in human endothelial cells under
proinflammatory conditions is governed by STAT-1 either directly or
indirectly through de novo synthesis of IRF-1. Moreover, decoy ODN
neutralization of these transcription factors may provide a novel
therapeutic option for interfering with CD40-CD40 ligand-mediated
inflammatory responses in vivo.
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