Institute of Anatomy, University of Kiel, 24118 Kiel, Germany.
Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
Sci Rep. 2017 Mar 9;7:44053. doi: 10.1038/srep44053.
Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.
可溶性白细胞介素-6 受体 (sIL-6R) 介导的转信号是一种与关节炎、神经退行性变和炎症性肠病等病理状况相关的重要促炎刺激物。sIL-6R 通过蛋白水解从其膜结合形式中产生，并且已经表明 A 型解整合素和金属蛋白酶 (ADAM) 10 和 17 在体外和体内进行受体的外结构域脱落。然而，在某些条件下，并非所有 sIL-6R 都可以归因于 ADAM10/17 活性。在这里，我们证明 IL-6R 是可溶性金属蛋白酶 α和膜结合金属蛋白酶 β 的脱落底物，导致具有生物活性的 sIL-6R，能够诱导 IL-6 转信号。我们确定了 IL-6R 茎区的 N 端部分内的切割，与 ADAM10/17 报道的切割位点不同。有趣的是，ADAM10/17 可以从细胞表面脱落膜结合的 meprin β，并且观察到可溶性 meprin β 不能脱落 IL-6R，这表明存在针对转信号的调节机制。此外，我们观察到人粒细胞中 meprin β 表达和 IL-6R 水平之间存在显著的负相关，为这种蛋白水解相互作用的体内功能提供了证据。
