Rothaug Michelle, Becker-Pauly Christoph, Rose-John Stefan
Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
Biochim Biophys Acta. 2016 Jun;1863(6 Pt A):1218-27. doi: 10.1016/j.bbamcr.2016.03.018. Epub 2016 Mar 23.
The cytokine interleukin-6 (IL-6) plays a critical role in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. Profound neuropathological changes, such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease are associated with increased IL-6 expression in brain. Increased nocturnal concentrations of serum IL-6 are found in patients with impaired sleep whereas IL-6-deficient mice spend more time in rapid eye movement sleep associated with dreaming. IL-6 is crucial in the differentiation of oligodendrocytes, regeneration of peripheral nerves and acts as a neurotrophic factor. It exerts its cellular effects through two distinct pathways which include the anti-inflammatory pathway involving the membrane-bound IL-6 receptor (IL-6R) expressed on selective cells, including microglia, in a process known as classical signaling that is also critical for bacterial defense. In classical signaling binding of IL-6 to the membrane-bound IL-6R activates the β-receptor glycoprotein 130 (gp130) and subsequent down-stream signaling. The alternative, rather pro-inflammatory pathway, shown to mediate neurodegeneration in mice, termed trans-signaling, depends on a soluble form of the IL-6R that is capable of binding IL-6 to stimulate a response on distal cells that express gp130. A naturally occurring soluble form of gp130 (sgp130) has been identified that can specifically bind and neutralize the IL-6R/IL-6 complex. Thus, trans-signaling is blocked but classical signaling is completely unaffected. A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases.
细胞因子白细胞介素-6（IL-6）在炎症性疾病的发病机制以及神经组织的生理稳态中发挥着关键作用。严重的神经病理变化，如多发性硬化症（MS）、帕金森病和阿尔茨海默病，都与大脑中IL-6表达增加有关。睡眠受损的患者夜间血清IL-6浓度升高，而IL-6缺陷小鼠在与做梦相关的快速眼动睡眠中花费的时间更多。IL-6在少突胶质细胞的分化、周围神经的再生中起关键作用，并作为一种神经营养因子。它通过两条不同的途径发挥细胞效应，其中包括抗炎途径，该途径涉及在包括小胶质细胞在内的选择性细胞上表达的膜结合IL-6受体（IL-6R），这一过程被称为经典信号传导，对细菌防御也至关重要。在经典信号传导中，IL-6与膜结合IL-6R的结合会激活β受体糖蛋白130（gp130）及随后的下游信号传导。另一种途径，即显示在小鼠中介导神经退行性变的促炎途径，称为转信号传导，它依赖于一种可溶性形式的IL-6R，该IL-6R能够结合IL-6以刺激表达gp130的远端细胞产生反应。已鉴定出一种天然存在的可溶性gp130（sgp130），它可以特异性结合并中和IL-6R/IL-6复合物。因此，转信号传导被阻断，但经典信号传导完全不受影响。一种经过修饰的重组二聚体形式的sgp130（sgp130Fc）已成功用于阻断小鼠的炎症过程，也可用于阐明神经疾病中的IL-6转信号传导。
