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首页> 外文期刊>The Biochemical Journal >Nuclear factor-kappa B motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells
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Nuclear factor-kappa B motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells

机译：核因子-κB基序和干扰素-α刺激的响应元件协同作用于内皮细胞中炎性细胞因子激活鸟苷酸结合蛋白-1表达

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摘要

The large GTPase GBP-1 (guanylate-binding protein-1) is a major IFN-gamma (interferon-gamma)-induced protein with potent anti-angiogenic activity in endothelial cells. An ISRE (IFN-alpha-stimulated response element) is necessary and sufficient for the induction of GBP-1 expression by IFN-gamma. Recently, we have shown that in vivo GBP-1 expression is strongly endothelial-cell-associated and is, in addition to IFN-gamma, also activated by interleukin-1beta and tumour necrosis factor-alpha, both in vitro and in vivo [Lubeseder-Martellato, Guenzi, Jorg, Topolt, Naschberger, Kremmer, Zietz, Tschachler, Hutzler, Schwemmle et al. (2002) Am. J. Pathol. 161, 1749-1759; Guenizi, Topolt, Cornali, Lubeseder-Martellato, Jorg, Matzen, Zietz, Kremmer, Nappi, Schwemmle et al. (2001) EMBO J. 20, 5568-5577]. In the present study, we identified a NF-kappaB (nuclear factor kappaB)-binding motif that, together with ISRE, is required for the induction of GBP-1 expression by interleukin-1 and tumour necrosis factor-alpha. Deactivation of the NF-kappaB motif reduced the additive effects of combinations of these cytokines with IFN-gamma by more than 50%. Importantly, NF-kappaB p50 rather than p65 activated the GBP-1 promoter. The NF-kappaB 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-kappaB inhibitors to support angiogenesis in inflammatory diseases including ischaemia.
机译：大的GTPase GBP-1（鸟苷酸结合蛋白-1）是主要的IFN-γ（干扰素-γ）诱导蛋白，在内皮细胞中具有强大的抗血管生成活性。 ISRE（IFN-α刺激的应答元件）对于通过IFN-γ诱导GBP-1表达是必要和充分的。最近，我们显示体内GBP-1的表达与内皮细胞密切相关，除IFN-γ外，在体外和体内均被白介素1beta和肿瘤坏死因子-α激活[Lubeseder -Martellato，Guenzi，Jorg，Topolt，Naschberger，Kremmer，Zietz，Tschachler，Hutzler，Schwemmle等。 （2002）Am。 J.Pathol。 161，1749-1759; Guenizi，Topolt，Cornali，Lubeseder-Martellato，Jorg，Matzen，Zietz，Kremmer，Nappi，Schwemmle等。 （2001）EMBO J. 20，5568-5577]。在本研究中，我们确定了NF-kappaB（核因子kappaB）结合基序，与ISRE一起，是由白介素-1和肿瘤坏死因子-α诱导GBP-1表达所必需的。 NF-κB基序的失活将这些细胞因子与IFN-γ的组合的累加效应降低了50％以上。重要的是，NF-κBp50而非p65激活了GBP-1启动子。在各种炎症相关基因的启动子区域中，与GBP-1启动子一样，在几乎相同的空间组织中检测到NF-kappaB基序和ISRE。因此，两个基序都可以构成调节GBP-1表达的协同炎症细胞因子应答模块。我们的发现可能会为使用NF-κB抑制剂支持包括缺血性在内的炎性疾病中的血管生成开辟新的前景。

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