Essential role of STAT3 in cytokine-driven NF-κB-mediated serum amyloid A gene expression
Essential role of STAT3 in cytokine-driven NF-κB-mediated serum amyloid A gene expression
复制标题
DOI：
10.1111/j.1365-2443.2005.00900.x
复制
发表时间：
2005-11-01
期刊：
影响因子：
2.1
通讯作者：
Yoshizaki, K
中科院分区：
文献类型：
--
作者：
Hagihara, K;Nishikawa, T;Yoshizaki, K
血清淀粉样蛋白A(SAA)是急性时相反应的敏感标志物，是淀粉样蛋白A(AA)(继发性)淀粉样变性中淀粉样原纤维的前体蛋白。由于血清SAA水平还与慢性炎症性疾病和冠状动脉疾病的活动性密切相关，从临床角度阐明SAA的确切诱发机制具有重要意义。尽管人类SAA基因在其启动子中没有显示典型的STAT3反应元件(RE)，但我们提供的证据表明，STAT3在细胞因子驱动的SAA表达中起着重要作用。在IL-1和IL-6(IL-1+6)刺激下，STAT3和核因子-kappa B(NF-kappa B)p65首先形成复合体，然后STAT3与SAA基因启动子NF-kappa B RE 3‘端的非共有序列相互作用。此外，p300与STAT3的共表达显著增强了SAA的转录活性。因此，STAT3、NF-kappa B p65和p300的复合体的形成对于IL-1+6刺激协同诱导SAA基因是必不可少的。我们的发现有望帮助了解AA淀粉样变性的炎症状态，通过血清SAA水平的正常化来帮助开发这种疾病的治疗策略。
Serum amyloid A (SAA) is a sensitive marker of acute-phase responses and known as a precursor protein of amyloid fibril in amyloid A (AA) (secondary) amyloidosis. Since the serum SAA level is also closely related to activity of chronic inflammatory disease and coronary artery disease, it is important to clarify the exact induction mechanism of SAA from the clinical point of view. Here we provide evidence that STAT3 plays an essential role in cytokine-driven SAA expression, although the human SAA gene shows no typical STAT3 response element (RE) in its promoters. STAT3 and nuclear factor kappa B (NF-kappa B) p65 first form a complex following interleukin (IL)-1 and IL-6 (IL-1+6) stimulation, after which STAT3 interacts with nonconsensus sequences at a 3' site of the SAA gene promoter's NF-kappa B RE. Moreover, co-expression of p300 with STAT3 dramatically enhances the transcriptional activity of SAA. The formation of a complex with STAT3, NF-kappa B p65, and p300 is thus essential for the synergistic induction of the SAA gene by IL-1+6 stimulation. Our findings are expected to aid the understanding of the inflammatory status of AA amyloidosis to aid development of a therapeutic strategy for this disease by means of normalization of serum SAA levels.