CD40 Regulation of IL-4 and IFN-g Effects on Fibroblasts

描述(摘自申请)：纤维化，过度沉积 细胞外基质是许多炎症性疾病的主要并发症， 包括以T细胞浸润为特征的风湿性疾病。 我们的目标是描述激活T细胞的新机制 调节成纤维细胞的增殖和胶原蛋白的产生。这项提议将 关注可溶性因子(IL-4和干扰素-7)与T细胞的相互作用 细胞-成纤维细胞接触(CD40-CD40L相互作用)调节 胶原蛋白的产生。 我们的总体假设是激活的T细胞之间的细胞表面相互作用 细胞和成纤维细胞调节促纤维化和抗纤维化的平衡 细胞因子的影响。这项研究的具体假设是IL-4和 干扰素-γ对成纤维细胞增殖和胶原合成的调节作用 通过CD40-CD40L相互作用，使整体平衡转向IL-4 效果。因此，我们认为CD40的结扎与IL-4具有协同作用 成纤维细胞中的信号，类似于众所周知的CD40之间的协同作用 结扎和IL-4对B细胞产生免疫球蛋白的调节。通过 协同效应：指具有较高幅度的两个因素的联合作用 而不是这两个因素单独作用的总和。我们还建议CD40 结扎可拮抗IFNy的抗纤维化作用。 这项提议将测试CD40连接如何在功能上影响 IL-4和干扰素-7之间的促/抗纤维化平衡。它还将检查 CD40结扎与IL-4相互作用的可能机制 尤其是通过激活细胞内的信号分子。 这项提议将涉及以下具体目标： 1.明确CD40结扎对IL-4和IL-4促纤维化作用的影响 干扰素-γ对成纤维细胞增殖和胶原的抗纤维化作用 制作。CD40结扎和IL-4的作用将在两个 细胞因子可以单独测试，也可以联合测试，或者在 细胞-成纤维细胞共培养。 2.探讨CD40结扎与IL-4对成纤维细胞的协同作用机制 扩散。实验将集中在蛋白酪氨酸激酶(PTK)信号上 转导途径，但也将测试调制的贡献 受体表达。 这项研究的意义在于它集中在新的机制上 调节纤维化的方法。免疫细胞。拟议的研究可能有助于我们的 了解T细胞在纤维化发生发展中的作用并导致 这些疾病的新治疗方法。

DESCRIPTION (Taken from the application): Fibrosis, the excessive deposition of extracellular matrix, is a major complication of many inflammatory disorders, including rheumatic diseases, which are characterized by T cell infiltration. Our goal is to characterize novel mechanisms by which activated T cells regulate fibroblast proliferation and collagen production. This proposal will focus on interactions between soluble factors (IL-4 and IFN-7) and T cell-fibroblast contacts (CD40-CD40L interactions) in the regulation of collagen production. Our overall hypothesis is that cell surface interactions between activated T cells and fibroblasts regulate the balance of pro-fibrotic and anti-fibrotic influences of cytokines. The specific hypothesis of this study is that IL-4 and IFN-y effects on fibroblast proliferation and collagen production are modulated by CD40-CD40L interaction, which shifts the overall balance toward IL-4 effects. Thus, we propose that CD40 ligation can be synergistic with IL-4 signals in fibroblasts, analogous to the well-known synergy between CD40 ligation and IL-4 m the regulation of immunoglobulin production by B cells. By synergy we designate a combined action of two factors that has higher amplitude than a sum of two effects of the factors alone. We also propose that CD40 ligation can be antagonistic to the antfibrotic effects of IFNy. This proposal will test how CD40 ligation functionally affects the pro-/anti-fibrotic balance between IL-4 and IFN-7. It will also examine potential mechanisms of interaction between CD40 ligation and IL-4, particularly through activation of intracellular signaling molecules. This proposal will address the following specific objectives: 1. Define the effects of CD40 ligation on the pro-fibrotic actions of IL-4 and anti-fibrotic actions of IFN-y on fibroblast proliferation and collagen production. The effects ofCD40 ligation and IL-4 will be defined when two cytokines are tested alone, in combination, or in the context oft cell-fibroblast co-cultures. 2. Determine mechanisms of synergy between CD40 ligation and IL-4 on fibroblast proliferation. Experiments will focus on protein.tyrosine kinase (PTK) signal transduction pathways, but will also test contribution of modulation of receptor expression. The significance of this research is that it focuses on novel mechanisms of regulating fibrosis by. immune cells. The proposed study may contribute to our understanding of the role T cells in the development of fibrosis and lead to novel therapeutic approaches in these diseases.