Interaction between Interleukin-6 (IL-6) and the growth hormone

生长激素（GH）/胰岛素样生长因子-I（IGF-I）轴是骨骼肌的重要调节因子 增长还已知IGF-I是骨骼肌适应增加的肌肉张力的重要介质。 加载中“促炎”细胞因子白细胞介素-6（IL-6）主要参与免疫应答 感染在许多情况下，已知IL-6的功能在骨骼肌中引起分解代谢状态。 有证据表明，IGF-I激活的细胞内信号通路的某些成分 和/或GH与IL-6刺激的信号传导共享。这些共同要素包括 JAK/STAT/SOCS信号和负反馈系统。奇怪的是，常见的锻炼方式 已显示增加血浆IL-6并抑制循环IGF-I。我们提供了初步数据， 表明，相对低剂量的IL-6，与人体运动后的水平相当， 引发骨骼肌分解代谢反应。我们假设肌肉中IL-6水平的升高与 并对GH和IGF-I在体内骨骼肌中的合成代谢作用产生负面影响。我们推测 IL-6介导这种影响的机制之一是通过激活SOCS反馈， IGF-I和GH介导的细胞内信号的改变。我们提出的实验旨在：1） 表征肌肉中的IL-6信号传导; 2）表征肌肉中的GH信号传导; 3）通过以下方式确定机制： IL-6与GH和IGF-I信号相互作用并改变GH和IGF-I信号; 4）确定IL-6与GH和IGF-I信号相互作用并改变GH和IGF-I信号的机制。 与骨骼肌相互作用并改变骨骼肌对增加负荷的适应; 5）确定机制 IL-6通过其影响骨骼肌的生长和发育。我们的方法是基于体内 我们团队开发的局部肌肉灌注模型。与目前在 文献中，这种方法允许直接（即，非全身性）将生长因子和细胞因子递送到 单一目标骨骼肌。在上一个融资期，我们证明了这种方法可以 用于操纵细胞内信号通路，并允许识别 介导对生长因子的反应。本提案中概述的研究将增加我们的理解 运动诱导IL-6升高对肌肉生长和适应的影响。

The growth hormone (GH) / insulin-like growth factor-l (IGF-I) axis is a powerful mediator of skeletal muscle growth. IGF-I is also known to be an important mediator of the adaptation of skeletal muscle to increased loading. The "proinflammatory" cytokine interleukin -6 (IL-6) is primarily involved with the immune response to infection. In many settings the functions of IL-6 are known to induse a catabolic state in skeletal muscle. There is evidence that some components of the intracellular signaling pathways that are activated by IGF-I and/or GH are shared with signaling stimulated by IL-6. These common elements include components of the JAK/STAT/SOCS signaling and negative feed back system. Paradoxically, common forms of exercise have been shown to increase plasma IL-6 and to depress circulating IGF-I. We present preliminary data which demonstrates that relatively low doses of IL-6, comparable to those seen in humans following exercise, can initiate a catabolic response in skeletal muscle. We hypothesize that elevated muscle levels of IL-6 interact with and negatively impact the anabolic effects of GH and IGF-I in skeletal muscle in vivo. We speculate that one of the mechanisms by which IL-6 mediates this impact is via the activation of SOCS feedback resulting in alterations in IGF-I and GH mediated intracellular signals. We propose experiments designed to:1) characterize IL-6 signaling in muscle; 2) characterize GH signaling in muscle; 3) identify the mechanisms by which IL-6 interacts with and alters GH and IGF-I signaling; 4) identify the mechanisms by which IL-6 interacts with and alters the adaptation of skeletal muscle to increased loading ; 5) identify the mechanisms by which IL-6 impacts the growth and development of skeletal muscle. Our approach is based on the in vivo local muscle infusion model developed by our team. In contrast to the methods currently found in the literature, this approach allows for the direct (i.e., non-systemic) delivery of growth factors and cytokines into a single targeted skeletal muscle. In our previous funding period we demonstrated that this approach can be used to manipulate intracellular signaling pathways and allow for the identification of mechanisms that mediate the response to growth factors. The studies outlined in this proposal will add to our understanding of the role of exercise induced elevations in IL-6 with regard to its impacts on muscle growth and adaptation.