Peters M, Meyer zum Büschenfelde K H, Rose-John S
Department of Medicine, Johannes Gutenberg-University of Mainz, Germany.
Immunol Lett. 1996 Dec;54(2-3):177-84. doi: 10.1016/s0165-2478(96)02669-7.
Interleukin-6 (IL-6) is considered an important mediator of acute inflammatory responses. Moreover, IL-6 functions as a differentiation and growth factor of hematopoietic precursor cells, B-cells, T-cells, keratinocytes, neuronal cells, osteoclasts and endothelial cells. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor (IL-6R) and a signal-transducing subunit (gp130). Soluble forms of both receptor components are generated by shedding and are found in patients with various diseases such as AIDS, rheumatoid arthritis and others. The function of the soluble IL-6R in vivo is unknown. To discriminate between the biologic function of hIL-6 alone and that of the hIL-6/hsIL-6R complex, mice transgenic for human IL-6, for the human soluble IL-6R and for both, human IL-6 and the human soluble IL-6R were analyzed and compared with nontransgenic littermates. While IL-6 transgenic mice exhibit elevated acute phase protein levels and develop plasmacytomas, hsIL-6R single transgenic mice are hypersensitized towards human IL-6, mounting an acute phase protein gene induction at significantly lower IL-6 dosages compared to control animals. Furthermore, in hsIL-6R transgenic mice, the acute phase response persists for a longer period of time and the IL-6 plasma half life was markedly prolonged. IL-6/sI1-6R mice, however, develop massive hepatosplenomegaly caused by extramedullary hematopoisis in these organs. In IL-6- and IL-6R-single transgenic mice, no such effects were observed. Our study discloses a novel biologic effect of the hIL-6/hsIL-6R complex, which is clearly distinct from that of hIL-6 alone. We provide evidence that the activation of the gp130 signal transducer represents a major stimulation of growth and differentiation of hematopoietic progenitor cells.
白细胞介素-6（IL-6）被认为是急性炎症反应的重要介质。此外，IL-6作为造血前体细胞、B细胞、T细胞、角质形成细胞、神经元细胞、破骨细胞和内皮细胞的分化及生长因子发挥作用。IL-6通过由特异性IL-6受体（IL-6R）和信号转导亚基（gp130）组成的受体复合物发挥其作用。两种受体成分的可溶性形式通过脱落产生，并在患有各种疾病（如艾滋病、类风湿性关节炎等）的患者体内发现。可溶性IL-6R在体内的功能尚不清楚。为了区分单独的人IL-6与人IL-6/人可溶性IL-6R复合物的生物学功能，对转人IL-6基因、转人可溶性IL-6R基因以及同时转人IL-6和人可溶性IL-6R基因的小鼠进行了分析，并与非转基因同窝小鼠进行比较。虽然IL-6转基因小鼠表现出急性期蛋白水平升高并发生浆细胞瘤，但人可溶性IL-6R单转基因小鼠对人IL-6高度敏感，与对照动物相比，在显著更低的IL-6剂量下即可诱导急性期蛋白基因。此外，在人可溶性IL-6R转基因小鼠中，急性期反应持续更长时间，且IL-6的血浆半衰期明显延长。然而，IL-6/可溶性IL-6R小鼠出现由这些器官的髓外造血引起的大量肝脾肿大。在IL-6和IL-6R单转基因小鼠中未观察到此类效应。我们的研究揭示了人IL-6/人可溶性IL-6R复合物的一种新的生物学效应，它明显不同于单独的人IL-6。我们提供的证据表明，gp130信号转导子的激活是造血祖细胞生长和分化的主要刺激因素。
