School of Molecular Bioscience, The University of Sydney, New South Wales 2006, Australia, Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona 08193, Spain, Department of Biochemistry, University of Kiel, D-24098 Kiel, Germany, and Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, 40225 Düsseldorf, Germany.
J Neurosci. 2014 Feb 12;34(7):2503-13. doi: 10.1523/JNEUROSCI.2830-13.2014.
IL-6 is implicated in the pathogenesis of various neuroinflammatory and neurodegenerative disorders of the CNS. IL-6 signals via binding to either the membrane bound IL-6Rα (classic signaling) or soluble (s)IL-6Ra (trans-signaling) that then form a complex with gp130 to activate the JAK/STAT signaling pathway. The importance of classic versus trans-signaling in mediating IL-6 actions in the living CNS is relatively unknown and was the focus of this investigation. Bigenic mice (termed GFAP-IL6/sgp130 mice) were generated with CNS-restricted, astrocyte-targeted production of IL-6 and coproduction of the specific inhibitor of IL-6 trans-signaling, human sgp130-Fc. Transgene-encoded IL-6 mRNA levels were similar in the brain of GFAP-IL6 and GFAP-IL6/sgp130 mice. However, GFAP-IL6/sgp130 mice had decreased pY(705)-STAT3 in the brain due to a reduction in the total number of pY(705)-STAT3-positive cells and a marked loss of pY(705)-STAT3 in specific cell types. Blockade of trans-signaling in the brain of the GFAP-IL6 mice significantly attenuated Serpina3n but not SOCS3 gene expression, whereas vascular changes including angiogenesis and blood-brain barrier leakage as well as gliosis were also reduced significantly. Hippocampal neurogenesis which was impaired in GFAP-IL6 mice was rescued in young GFAP-IL6 mice with cerebral sgp130 production. Finally, degenerative changes in the cerebellum characteristic of GFAP-IL6 mice were absent in GFAP-IL6/sgp130 mice. The findings indicate that in the CNS: (1) sgp130 is able to block IL-6 trans-signaling, (2) trans-signaling is important for IL-6 cellular communication with selective cellular and molecular targets, and (3) blocking of trans-signaling alleviates many of the detrimental effects of IL-6.
白细胞介素 6（IL-6）参与了中枢神经系统（CNS）各种神经炎症和神经退行性疾病的发病机制。IL-6 通过与膜结合的白细胞介素 6 受体 α（经典信号）或可溶性（s）白细胞介素 6 受体 α（转信号）结合而发出信号，然后与 gp130 形成复合物，激活 JAK/STAT 信号通路。经典信号与转信号在介导活中枢神经系统中 IL-6 作用的相对重要性尚不清楚，这是本研究的重点。双基因小鼠（命名为 GFAP-IL6/sgp130 小鼠）通过 CNS 限制、星形胶质细胞靶向产生 IL-6 和特异性抑制 IL-6 转信号的人 sgp130-Fc 的共产生而产生。GFAP-IL6 和 GFAP-IL6/sgp130 小鼠大脑中的转基因编码 IL-6 mRNA 水平相似。然而，由于 pY(705)-STAT3 阳性细胞总数减少和特定细胞类型中 pY(705)-STAT3 的明显丢失，GFAP-IL6/sgp130 小鼠大脑中的 pY(705)-STAT3 减少。在 GFAP-IL6 小鼠的大脑中阻断转信号显著减弱了 Serpina3n 但不 SOCS3 基因表达，而血管变化包括血管生成和血脑屏障渗漏以及神经胶质增生也显著减少。GFAP-IL6 小鼠的海马神经发生受损，在具有大脑 sgp130 产生的年轻 GFAP-IL6 小鼠中得到挽救。最后，GFAP-IL6 小鼠小脑的退行性变化在 GFAP-IL6/sgp130 小鼠中不存在。这些发现表明，在中枢神经系统中：（1）sgp130 能够阻断 IL-6 转信号，（2）转信号对于 IL-6 与选择性细胞和分子靶标的细胞间通讯很重要，（3）阻断转信号减轻了 IL-6 的许多不利影响。
