The Th2 gene cluster unraveled: role of RHS6.
The Th2 gene cluster unraveled: role of RHS6.
复制标题
揭示 Th2 基因簇：RHS6 的作用。
作者：
Flayer,CH;Haczku,A
过敏性气道炎症是哮喘的一个主要病理特征，是由 IL-4、IL-5 和 IL-13 的产生驱动的。这些介质一起被称为“Th2 细胞因子”，因为它们的主要产生者是分化的 CD4+ T 辅助细胞 2 (Th2) 细胞。 IL-4 驱动过敏致敏、IgE 产生和 Th2 细胞分化。 IL-5 对于肺部嗜酸性粒细胞的积累和激活至关重要。 IL-13 在组织重塑以及气道高反应性的发生和进展中具有多效性作用。由于这些主要作用，Th2 细胞因子被确定为治疗哮喘的潜在治疗靶点，并有望在该领域取得成功 (1)。不幸的是，抗 Th2 细胞因子疗法的效果普遍较差，尽管最近在识别对这些疗法有反应的内型特定患者方面取得的进展有助于提高疗效 (2)。这些药物可能在临床上举步维艰，因为（除了它们独特的作用之外）Th2 细胞因子具有许多重叠的功能。因此，调节多种 Th2 细胞因子产生的转录因子等上游治疗靶点是否可能会发挥更好的作用 (3, 4)？为了探索这种选择，我们必须提高对控制 Th2 细胞因子基因转录的机制的理解，特别是在过敏性气道炎症期间。IL-4、IL-13 和 IL-5 的基因聚集在小鼠 11 号染色体上的 120 kb 区域和人类 5 号染色体上的 160 kb 区域。 Th2 细胞因子以 T 细胞谱系特异性方式表达，因此它们的转录受到转录因子和其他调节因子的复杂网络的协调调节，这些调节因子与基因启动子结合以激活和/或抑制它们。此过程伴随着染色质结构的变化 (5)。事实上，Th2 细胞因子基因座作为免疫基因染色质构象的模型系统已得到深入研究。 DNA 如何在细胞核中组织成三维结构以及其功能后果是什么，一直是细胞和分子生物学中最古老的问题之一 (6)。
Allergic airway inflammation, a cardinal pathological feature of asthma is driven by production of IL-4, IL-5, and IL-13. Together, these mediators are referred to as ‘Th2 cytokines’ because a major producer of them is the differentiated CD4+ T-helper 2 (Th2) cell. IL-4 drives allergic sensitization, IgE production, and Th2 cell differentiation. IL-5 is critical in eosinophil accumulation and activation in the lung. IL-13 has pleiotropic effects in tissue remodeling and the development and progression of airway hyper-responsiveness. Because of these major effects, Th2 cytokines were identified as potential therapeutic targets for the treatment of asthma with a great hope in the field for their success (1). Unfortunately, the anti-Th2 cytokine therapeutics had generally poor results, although recent advances in identifying specific patients with endotypes responsive to these therapeutics have helped efficacy (2). These drugs likely struggled in the clinic because (in addition to their unique effects) the Th2 cytokines have numerous overlapping functions. Would it be possible therefore that upstream therapeutic targets like transcription factors that regulate multiple Th2 cytokine production would work better (3, 4)? To explore such option, it is imperative that we improve our understanding of the mechanisms that control the transcription of Th2 cytokine genes, especially during allergic airway inflammation.The genes for IL-4, IL-13, and IL-5 are clustered in a 120-kb region on chromosome 11 in mice and a 160-kb region on chromosome 5 in humans. Th2 cytokines are expressed in a T-cell lineage-specific fashion and their transcription is therefore coordinately regulated by a complex network of transcription factors and other regulators that bind to gene promoters to activate and/or repress them. This process is accompanied by changes in chromatin structure (5). Indeed, the Th2 cytokine locus has been intensively studied as a model system of chromatin conformation of immune genes. How DNA is organized into three-dimensional structures in the nucleus and what are the functional consequences have been among the oldest questions in cell and molecular biology (6).