Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses
Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses
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DOI：
10.1046/j.1432-1327.2001.01867.x
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发表时间：
2001-01-01
期刊：
影响因子：
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通讯作者：
Rose-John, S
中科院分区：
文献类型：
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作者：
Jostock, T;Müllberg, J;Rose-John, S
响应于白细胞介素-6（IL-6）的信号转导需要细胞因子与其受体（IL-6 R）的结合以及随后的信号转导物gp 130的同源二聚化。IL-6和可溶性IL-6 R（sIL-6 R）的复合物触发gp 130的二聚化并诱导不表达膜结合IL-6 R的细胞的应答。天然存在的可溶性gp 130（sgp 130）可以在与IL-6和sIL-6 R的三元复合物中发现。我们构建了重组sgp 130蛋白，该蛋白与IL-6和sIL-6 R复合物结合，并抑制IL-6/sIL-6 R诱导的表达gp 130的BAF/3细胞增殖。令人惊讶的是，sgp 130蛋白不影响IL-6刺激的表达gp 130和膜结合的IL-6 R的BAF/3细胞的增殖，表明sgp 130不干扰IL-6与细胞表面上的IL-6 R结合。此外，sgp 130部分抑制白血病抑制因子（LIF）和制瘤素M（OSM）诱导的增殖，尽管在较高的浓度。重组sgp 130蛋白可阻断sIL-6 R对克罗恩病患者固有层细胞的抗凋亡作用。我们的结论是，sgp 130是IL-6反应的天然抑制剂依赖于sIL-6 R。此外，重组sgp 130有望成为特异性阻断其中存在sIL-6 R信号转导应答的疾病状态（例如克罗恩病）的有价值的治疗工具。
Signal transduction in response to interleukin-6 (IL-6) requires binding of the cytokine to its receptor (IL-6R) and subsequent homodimerization of the signal transducer gp130. The complex of IL-6 and soluble IL-6R (sIL-6R) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R. Naturally occurring soluble gp130 (sgp130) can be found in a ternary complex with IL-6 and sIL-6R. We created recombinant sgp130 proteins that showed binding to IL-6 in complex with sIL-6R and inhibited IL-6/sIL-6R induced proliferation of BAF/3 cells expressing gp130. Surprisingly, sgp130 proteins did not affect IL-6 stimulated proliferation of BAF/3 cells expressing gp130 and membrane bound IL-6R, indicating that sgp130 did not interfere with IL-6 bound to IL-6R on the cell surface. Additionally, sgp130 partially inhibited proliferation induced by leukemia inhibitory factor (LIF) and oncostatin M (OSM) albeit at higher concentrations. Recombinant sgp130 protein could be used to block the anti-apoptotic effect of sIL-6R on lamina propria cells from Crohn disease patients. We conclude that sgp130 is the natural inhibitor of IL-6 responses dependent on sIL-6R. Furthermore, recombinant sgp130 is expected to be a valuable therapeutic tool to specifically block disease states in which sIL-6R transsignaling responses exist, e.g. in morbus Crohn disease.