TNF biology, pathogenic mechanisms and emerging therapeutic strategies.
TNF biology, pathogenic mechanisms and emerging therapeutic strategies.
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DOI：
10.1038/nrrheum.2015.169
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Ivashkiv LB
中科院分区：
文献类型：
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作者：
Kalliolias GD;Ivashkiv LB
TNF是一种多效性细胞因子，在体内平衡和疾病发病机制中具有重要作用。最近的发现为TNF生物学提供了新的见解，为TNF介导的疾病的治疗方法的发展引入了新的概念。TNF受体信号传导的模型已经扩展到包括线性泛素化和与不同功能结果（如炎症、凋亡和坏死性凋亡）相关的不同信号传导复合物的形成。我们对TNF诱导的基因表达的理解已经丰富了表观遗传机制的发现和概念相关的细胞启动，耐受性和诱导的“短期转录记忆”。不同的稳态或致病性TNF诱导的信号传导途径的鉴定引入了选择性抑制TNF的有害作用同时保持其稳态生物活性用于治疗目的的概念。在这篇综述中，我们提出了TNF在体内平衡和炎症性疾病发病机制中的作用的分子机制，并讨论了新的策略，以推进治疗TNF介导的疾病的治疗模式。
TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of ‘short-term transcriptional memory’. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.