MECHANISM OF MATRIX MODULATION OF IL 1 SIGNALING

IL-1是炎症反应的中枢介质。IL-1与其受体的结合 激活两个不同的通路MAP-2和NF-kappa-B，但 信号转导的初始事件尚不清楚。对这一效应的研究 对细胞外基质代谢的影响显示IL-1对细胞外基质代谢的调节 蛋白多糖和胶原mRNA水平依赖于纤维连接蛋白 依恋。IL-1受体定位于局部粘连和IL-1结合 导致细胞-基质相互作用的改变和 细胞骨架。我们发现IL-1受体结合受以下因素影响 纤维连接蛋白附着物。此外，我们正在进行的研究表明，IL-1 纤维连接蛋白影响MAP-2和NF-kappaB的激活 依恋。此类更改可能是由激活其他 干扰IL-1诱导激活的信号通路。在……里面 此外，它们可能是基质敏感信使变化的结果 在IL-1激活途径的上游，或在MAP-2水平上 蛋白激酶和核因子-kappaB的表达。目前所描述的实验 提案将确定矩阵/单元所涉及的机制- 依恋对IL-1信号转导的影响。我们将决定 无论是基质诱导的激酶，还是粘着斑活化的激酶 P125FAK，影响IL-1诱导的信号通路。此外，我们还将研究 第二信使，在IL-1诱导途径的上游或被激活 其他细胞因子和生长因子，特别是那些具有特定功能的 对结构关系的影响，并决定细胞-基质的影响 在他们的监管上的互动。此外，我们将确定这些变化是否 MAP-2的质变可以部分解释In信号转导 激酶和核因子-kappaB。最后，我们将使用胶原蛋白启动子来 确定-信令中的这些变化实际上是导致 通过研究基质诱导生物反应的变化 核因子-kappaB和AP-1缺失或改变对突变体的诱导作用 结合部位。这些研究将增加我们对 细胞因子与细胞外信号的相互依赖 矩阵通过确定所涉及的路径和机制(S)，因此， 有助于进一步阐明炎症过程中IL-1的调节。

IL-1 is a central mediator of inflammation. IL-1 binding to its receptor activates two separate pathways map-2 kinase and NF-kappa-B, but the initial events of signal transduction are not known. Studies on the effect on the extracellular matrix metabolism show that IL-1 regulation of proteoglycans and collagen mRNA levels are dependent on fibronectin attachment. IL-1 receptors are located at focal adhesions and IL-1 binding causes changes in cell-matrix interaction and alterations in the cytoskeleton. We have found that IL-1 receptor binding is affected by fibronectin attachment. Further, our ongoing studies show that IL-1 activation of both map-2 kinase and NF-kappaB are affected by fibronectin attachment. Such changes could be caused by activation of additional signaling pathways interfering with the IL-1 induced activation. In addition, they could be a result of change in matrix sensitive messengers in the IL-1 activated pathway either upstream, or at the level of map-2 kinase and NF-Kappa-B respectively. Experiments described in the present proposal will determine the mechanisms involved in the matrix/cell- attachment induced effect on IL-1 signal transduction. We will determine whether the matrix induced kinase, the focal adhesion activated kinase p125FAK, influences the IL-1 induced pathways. In addition, we will study second messengers, upstream in the IL-1 induced pathway or activated by other cytokines and growth factors, in particular those with specific effects on structural relations, and determine the effect of cell-matrix interaction on their regulation. Further, we will determine if the changes in signaling can be partly explained by qualitative alterations of map-2 kinase and NF-kappaB. Finally, we will use the collagen promotor to determine that-these changes in signaling actually are responsible for the induced alterations in the biological response by studying the matrix induced effect in mutants with lacking or altered NF-kappaB and AP-1 binding sites. These studies will increase our understanding of interdependence of signaling between cytokines and the extracellular matrix by determining the pathways and the mechanism(s) involved and thus, help further clarify the regulation of IL-1 during inflammation.