Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
Curr Biol. 2021 Apr 26;31(8):1780-1787.e6. doi: 10.1016/j.cub.2021.01.080. Epub 2021 Feb 19.
Developmental transitions, such as puberty or metamorphosis, are tightly controlled by steroid hormones and can be delayed by the appearance of growth abnormalities, developmental tumors, or inflammatory disorders such as inflammatory bowel disease or cystic fibrosis. Here, we used a highly inflammatory epithelial model of malignant transformation in Drosophila to unravel the role of Upd3-a cytokine with homology to interleukin-6-and the JAK/STAT signaling pathway in coupling inflammation to a delay in metamorphosis. We present evidence that Upd3 produced by malignant and nearby cell populations signals to the prothoracic gland-an endocrine tissue primarily dedicated to the production of the steroid hormone ecdysone-to activate JAK/STAT and bantam microRNA (miRNA) and to delay metamorphosis. Upd cytokines produced by the tumor site contribute to increasing the systemic levels of Upd3 by amplifying its expression levels in a cell-autonomous manner and by inducing Upd3 expression in neighboring tissues in a non-autonomous manner, culminating in a major systemic response to prevent larvae from initiating pupa transition. Our results identify a new regulatory network impacting on ecdysone biosynthesis and provide new insights into the potential role of inflammatory cytokines and the JAK/STAT signaling pathway in coupling inflammation to delays in puberty.
发育转变，如青春期或变态，受类固醇激素的严格控制，并且可能因生长异常、发育性肿瘤或炎症性疾病（如炎症性肠病或囊性纤维化）的出现而延迟。在这里，我们使用了果蝇中一种高度炎症的恶性转化上皮模型，以揭示 Upd3（一种与白细胞介素-6 同源的细胞因子）和 JAK/STAT 信号通路在将炎症与变态延迟相耦合中的作用。我们提供的证据表明，来自恶性和附近细胞群体的 Upd3 信号转导至前胸腺——一种主要致力于产生类固醇激素蜕皮激素的内分泌组织——以激活 JAK/STAT 和 bantam 微 RNA（miRNA）并延迟变态。肿瘤部位产生的 Upd 细胞因子通过以细胞自主性方式放大其表达水平并以非自主性方式诱导邻近组织中 Upd3 的表达，从而增加系统中 Upd3 的水平，从而导致对幼虫启动蛹转变的全身性反应，从而有助于增加系统中 Upd3 的水平。我们的研究结果确定了一个新的调控网络，该网络影响蜕皮激素的生物合成，并为炎症细胞因子和 JAK/STAT 信号通路在将炎症与青春期延迟相耦合中的潜在作用提供了新的见解。
