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Nuclear factor-kB motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells.
Biochem. J. 379, 409-420 (2004)
The large GTPase GBP-1 (guanylate-binding protein-1) is a major IFN-γ (interferon-γ)-induced protein with potent anti-angiogenic activity in endothelial cells. An ISRE (IFN-α-stimulated response element) is necessary and sufficient for the induction of GBP-1 expression by IFN-γ. Recently, we have shown that in vivo GBP-1 expression is strongly endothelial-cell-associated and is, in addition to IFN-γ, also activated by interleukin-1β and tumour necrosis factor-α, both in vitro and in vivo [Lubeseder-Martellato, Guenzi, Jörg, Töpolt, Naschberger, Kremmer, Zietz, Tschachler, Hutzler, Schwemmle et al. (2002) Am. J. Pathol. 161, 1749–1759; Guenzi, Töpolt, Cornali, Lubeseder-Martellato, Jörg, Matzen, Zietz, Kremmer, Nappi, Schwemmle et al. (2001) EMBO J. 20, 5568–5577]. In the present study, we identified a NF-κB (nuclear factor κB)-binding motif that, together with ISRE, is required for the induction of GBP-1 expression by interleukin-1β and tumour necrosis factor-α. Deactivation of the NF-κB motif reduced the additive effects of combinations of these cytokines with IFN-γ by more than 50%. Importantly, NF-κB p50 rather than p65 activated the GBP-1 promoter. The NF-κB motif and ISRE were detected in an almost identical spatial organization, as in the GBP-1 promoter, in the promoter regions of various inflammation-associated genes. Therefore both motifs may constitute a cooperative inflammatory cytokine response module that regulates GBP-1 expression. Our findings may open new perspectives for the use of NF-κB inhibitors to support angiogenesis in inflammatory diseases including ischaemia.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
guanylate-binding protein-1; human umbilical-vein endothelial cells; inflammation; interleukin-1; nuclear factor kB; tumour necrosis factor
ISSN (print) / ISBN
0264-6021
e-ISSN
1470-8728
Zeitschrift
Biochemical Journal / Reviews
Quellenangaben
Band: 379,
Heft: 2,
Seiten: 409-420
Verlag
Portland Press
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed