Yanagibashi Tsutomu, Satoh Mitsuo, Nagai Yoshinori, Koike Masamichi, Takatsu Kiyoshi
Toyama Prefectural Institute of Pharmaceutical Research, 17-1 Nakataikouyama, Imizu City, Toyama 939-0363, Japan; Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan.
Kyowa Hakko Kirin Co., Ltd., Otemachi Finamcial City Grand Cube, 1-9-2, Chiyoda-ku, Tokyo 100-8185, Japan.
Cytokine. 2017 Oct;98:59-70. doi: 10.1016/j.cyto.2016.11.011.
T helper 2 cells produce a number of cytokines including inteleukin (IL)-5, IL-4 and IL-13. Group 2 innate lymphoid cells (ILC2s) also produce IL-5 under sterile conditions. IL-5 is interdigitating homodimeric glycoprotein and a member of the four α helical bundle motifs conserved among hematopoietic cytokines. IL-5 exerts its effects on target cells via IL-5 receptor (IL-5R), composed of an IL-5R α and βc subunit. The membrane proximal proline-rich motif of the cytoplasmic domain of both IL-5R α and βc subunits is essential for IL-5 signal transduction. Although IL-5 was initially identified by its ability to support the growth and terminal differentiation of mouse B cells into antibody-secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells. For example, IL-5 is now recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Overexpression of IL-5 in mouse significantly increases eosinophil numbers and antibody levels in vivo, while mice lacking a functional gene for IL-5 or IL-5R display developmental and functional impairments in B cell and eosinophil lineages. In mice, the role of the IL-5/IL-5R system in the production and secretion of Immunoglobulin (Ig) M and IgA in mucosal tissues has been reported. Although eosinophils protect against invading pathogens including virus, bacteria and helminthes, they are also involved in the pathogenesis of various diseases, such as food allergy, asthma, and inflammatory bowel diseases. The recent expansion in our understanding in the context of IL-5 and IL-5-producing ILC2s in eosinophil activation and the pathogenesis of eosinophil-dependent inflammatory diseases has led to advances in therapeutic options. A new therapy currently under invetigarion in clinical trials uses humanized monoclonal antibodies against IL-5 or the IL-5R. In this review, we summarize our current understanding of the functions of IL-5 and its receptor, the innate regulation of IL-5-producing cells, and therapeutic potential of anti-IL-5 and anti-eosinophil (IL-5R) antibodies.
辅助性T细胞2产生多种细胞因子，包括白细胞介素（IL）-5、IL-4和IL-13。2型固有淋巴细胞（ILC2s）在无菌条件下也产生IL-5。IL-5是相互交错的同型二聚体糖蛋白，是造血细胞因子中保守的四个α螺旋束基序成员之一。IL-5通过由IL-5Rα和βc亚基组成的IL-5受体（IL-5R）对靶细胞发挥作用。IL-5Rα和βc亚基细胞质结构域的膜近端富含脯氨酸基序对于IL-5信号转导至关重要。尽管IL-5最初是因其支持小鼠B细胞生长和终末分化为抗体分泌细胞的能力而被鉴定出来的，但重组IL-5对各种靶细胞具有多效性活性。例如，IL-5现在被认为是小鼠和人类嗜酸性粒细胞主要的成熟和分化因子。小鼠体内IL-5的过表达显著增加嗜酸性粒细胞数量和抗体水平，而缺乏IL-5或IL-5R功能基因的小鼠在B细胞和嗜酸性粒细胞谱系中表现出发育和功能障碍。在小鼠中，已经报道了IL-5/IL-5R系统在黏膜组织中免疫球蛋白（Ig）M和IgA产生和分泌中的作用。尽管嗜酸性粒细胞可抵御包括病毒、细菌和蠕虫在内的入侵病原体，但它们也参与各种疾病的发病机制，如食物过敏、哮喘和炎症性肠病。最近我们对IL-5和产生IL-5的ILC2s在嗜酸性粒细胞活化和嗜酸性粒细胞依赖性炎症性疾病发病机制方面的理解不断扩展，这导致了治疗选择的进展。目前正在临床试验中研究的一种新疗法使用针对IL-5或IL-5R的人源化单克隆抗体。在本综述中，我们总结了目前对IL-5及其受体功能、产生IL-5细胞的固有调节以及抗IL-5和抗嗜酸性粒细胞（IL-5R）抗体治疗潜力的理解。
