Targeting IL-6 trans-signalling: past, present and future prospects.
Targeting IL-6 trans-signalling: past, present and future prospects.
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DOI：
10.1038/s41577-023-00856-y
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发表时间：
2023-10
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影响因子：
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白细胞介素-6（IL-6）是一种重要的免疫调节细胞因子，影响多种疾病的发病机制，包括自身免疫性疾病、慢性炎症和癌症。经典的IL-6信号传导涉及IL-6与膜结合的IL-6受体α-亚基（下文称为“mIL-6 R”）和糖蛋白130（gp 130）信号转导亚基的结合。相比之下，在IL-6 trans-signaling中，IL-6和可溶性形式的IL-6受体（sIL-6 R）的复合物通过膜结合的gp 130发出信号。IL-6信号传导的第三种模式-称为簇信号传导-涉及一个细胞上的膜结合IL-6-mIL-6 R的预形成复合物激活靶细胞上的gp 130亚基。已经开发了阻断所有三种形式的IL-6信号传导的抗体和小分子，但是在过去的十年中，IL-6反式信号传导已经成为IL-6促进疾病发病机制的主要途径。IL-6反式信号传导的第一个选择性抑制剂sgp 130已在各种临床前疾病模型中显示出治疗潜力，而sgp 130 Fc变体olamkicept在炎症性肠病的II期临床研究中具有有希望的结果。技术发展已经导致下一代sgp 130变体对IL-6反式信号传导具有增加的亲和力和选择性，沿着间接策略来阻断IL-6反式信号传导。在这里，我们总结了我们目前对IL-6介导的信号传导的生物学结果的理解，以及在临床中靶向该途径的潜力。本综述详细介绍了白细胞介素-6（IL-6）信号转导通路的发现以及随后特异性抑制该通路的生物制剂的开发。新出现的证据表明，特异性靶向IL-6反式信号传导可以降低IL-6的病理性疾病促进活性，而不会阻断IL-6在感染和组织修复中的保护作用。
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed ‘mIL-6R’) and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling — known as cluster signalling — involves preformed complexes of membrane-bound IL-6–mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic. This Review details the discovery of the interleukin-6 (IL-6) trans-signalling pathway and the subsequent development of biologics that specifically inhibit this pathway. Emerging evidence suggests that specifically targeting IL-6 trans-signalling can reduce pathological disease-promoting activities of IL-6 without blocking the protective actions of IL-6 in infection and tissue repair.
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影响因子：
13.6
作者：
Allanki S;Strilic B;Scheinberger L;Onderwater YL;Marks A;Günther S;Preussner J;Kikhi K;Looso M;Stainier DYR;Reischauer S
通讯作者：
Reischauer S
影响因子：
8.8
作者：
Barkhausen, Tanja;Tschernig, Thomas;Waetzig, Georg H.
通讯作者：
Waetzig, Georg H.
DOI：
10.1016/0167-5699(90)90139-z
发表时间：
1990-10-01
期刊：
IMMUNOLOGY TODAY
影响因子：
--
作者：
BAZAN, JF
通讯作者：
BAZAN, JF
影响因子：
24.5
作者：
Danese S;Vermeire S;Hellstern P;Panaccione R;Rogler G;Fraser G;Kohn A;Desreumaux P;Leong RW;Comer GM;Cataldi F;Banerjee A;Maguire MK;Li C;Rath N;Beebe J;Schreiber S
通讯作者：
Schreiber S
影响因子：
33.7
作者：
Choy, Ernest H.;De Benedetti, Fabrizio;Kishimoto, Tadamitsu
通讯作者：
Kishimoto, Tadamitsu