Department of Medicine 1, University of Erlangen-Nürnberg, Kussmaul Research Campus & Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), University of Erlangen-Nürnberg, Germany.
Cytokine Growth Factor Rev. 2019 Feb;45:1-8. doi: 10.1016/j.cytogfr.2018.12.002. Epub 2018 Dec 12.
Studies in recent years have identified a pivotal role of the cytokine IL-23 in the pathogenesis of inflammatory bowel diseases (IBD: Crohn´s disease, ulcerative colitis) and colitis-associated colon cancer. Genetic studies revealed that subgroups of IBD patients have single nucleotide polymorphisms in the IL-23R gene suggesting that IL-23R signaling affects disease susceptibility. Furthermore, increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients. Moreover, in several murine models of colitis, suppression of IL-12/IL-23 p40, IL-23 p19 or IL-23R function led to marked suppression of gut inflammation. This finding was associated with reduced activation of IL-23 target cells such as T helper 17 cells, innate lymphoid cells type 3, granulocytes and natural killer cells as well as with impaired production of proinflammatory cytokines. Based on these findings, targeting of IL-23 emerges as important concept for suppression of gut inflammation and inflammation-associated cancer growth. Consistently, neutralizing antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn´s disease and pilot studies in ulcerative colitis are ongoing. These findings underline the crucial regulatory role of IL-23 in chronic intestinal inflammation and colitis-associated cancer and indicate that therapeutic strategies aiming at IL-23 blockade may be of key relevance for future therapy of IBD patients.
近年来的研究表明，细胞因子 IL-23 在炎症性肠病（IBD：克罗恩病、溃疡性结肠炎）和结肠炎相关结肠癌的发病机制中起着关键作用。遗传研究表明，IBD 患者亚组存在 IL-23R 基因的单核苷酸多态性，提示 IL-23R 信号通路影响疾病易感性。此外，在各种结肠炎、结肠炎相关癌症和 IBD 患者的小鼠模型中观察到巨噬细胞、树突状细胞或粒细胞产生的 IL-23 增加。此外，在几种结肠炎的小鼠模型中，抑制 IL-12/IL-23 p40、IL-23 p19 或 IL-23R 功能导致肠道炎症明显抑制。这一发现与 IL-23 靶细胞如辅助性 T 细胞 17 细胞、先天淋巴细胞 3 型、粒细胞和自然杀伤细胞的活化减少以及促炎细胞因子产生受损有关。基于这些发现，靶向 IL-23 成为抑制肠道炎症和炎症相关癌症生长的重要概念。一致地，针对 IL-12/IL-23 p40 和 IL-23 p19 的中和抗体已成功用于克罗恩病的临床试验，并正在进行溃疡性结肠炎的试点研究。这些发现强调了 IL-23 在慢性肠道炎症和结肠炎相关癌症中的关键调节作用，并表明旨在阻断 IL-23 的治疗策略可能对未来 IBD 患者的治疗具有重要意义。
