TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-1 STIMULATE THE HUMAN IMMUNODEFICIENCY VIRUS ENHANCER BY ACTIVATION OF THE NUCLEAR FACTOR KAPPA-B
TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-1 STIMULATE THE HUMAN IMMUNODEFICIENCY VIRUS ENHANCER BY ACTIVATION OF THE NUCLEAR FACTOR KAPPA-B
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DOI：
10.1073/pnas.86.7.2336
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发表时间：
1989-04-01
影响因子：
11.1
通讯作者：
NABEL, GJ
中科院分区：
文献类型：
--
作者：
OSBORN, L;KUNKEL, S;NABEL, GJ
表面膜受体的肽激素结合导致相关靶细胞内特定基因的转录。这些信号如何被转导以改变基因表达在很大程度上是未知的，但这一机制可能涉及一系列激活细胞核中调节转录的因子的酶促步骤。我们现在证明了两种不同的肽激素或细胞因子刺激人类免疫缺陷病毒增强子，这种作用是由核因子（NF） .kappa介导的。B(结合。kappa的核因子。免疫球蛋白轻链基因增强子)。这些细胞因子，肿瘤坏死因子。白细胞介素1，作用于多种细胞类型，代表了八种细胞因子中唯一自然产生的这种转录因子的激活因子。尽管NF -.kappa。12-肉豆蔻酸13-乙酸佛波、肿瘤坏死因子可刺激B结合。通过一个独立的机制，诱导NF-.kappa。B在HT-2细胞中的结合，在12-肉豆蔻酸13-醋酸phorbol中没有表现出增加的结合，并在Jurkat t淋巴瘤细胞中引起超诱导。肿瘤坏死因子。与12-肉豆蔻酸13-醋酸佛波酯相比，它对T细胞的选择性更强，对EL-4细胞淋巴因子的产生没有影响，同时可诱导NF-.kappa.B。这些发现提示，在不激活淋巴因子分泌的情况下，可以在T细胞中诱导人类免疫缺陷病毒基因表达，这些细胞因子在激活潜伏性人类免疫缺陷病毒感染中的作用值得进一步的临床评价。最后，细胞膜表面的结合和特定转录因子的刺激之间的联系应该有助于确定这些细胞因子激活途径的中间体。
Binding of peptide hormones of surface membrane receptors leads to the transcription of specific genes within relevant target cells. How these signals are transduced to alter gene expression is largely unknown, but this mechanism probably involves a sequence of enzymatic steps that activate factors in the nucleus that modulate transcription. We now demonstrate that two different peptide hormones, or cytokines, stimulate the human immunodeficiency virus enhancer, and this effect is mediated by nuclear factor (NF) .kappa.B (nuclear factor that binds the .kappa. immunoglobulin light chain gene enhancer). These cytokines, tumor necrosis factor .alpha. and interleukin 1, act on multiple cell types and represent the only naturally occurring activators of this transcription factor among eight cytokines examined. Although NF-.kappa.B binding can be stimulated by phorbol 12-myristate 13-acetate, tumor necrosis factor .alpha. acts through an independent mechanism, inducing NF-.kappa.B binding in HT-2 cells, which did not show increased binding in response to phorbol 12-myristate 13-acetate, and causing superinduction in Jurkat T-lymphoma cells. Tumor necrosis factor .alpha. is also a more selective of T cells than phorbol 12-myristate 13-acetate, having no effect on lymphokine production in EL-4 cells at the same time it induces NF-.kappa.B. These findings suggest that human immunodeficiency virus gene expression can be induced in T cells without activating lymphokine secretion and that the role of these cytokines in the activation of latent human immunodeficiency virus infection deserves further clinical evaluation. Finally, this link between binding at the surface membrane and stimulation of a specific transcription factor should help define intermediates for these cytokine activation pathways.