KLF4, TGF-b1, and transplantation arteriosclerosis

描述(申请人提供)：移植相关动脉硬化(TAA)是心脏移植后存活超过一年的受者的主要死亡原因。TAA的特点是炎性细胞浸润，随后形成弥漫的、同心的新生内膜，其中平滑肌细胞和巨噬细胞聚集。免疫系统的细胞--尤其是巨噬细胞--在TAA中起着关键作用。活化的巨噬细胞通过阐述炎症细胞因子、摄取氧化脂质和释放蛋白水解酶，在TAA中起关键作用。因此，确定调节巨噬细胞激活的因素至关重要。Kruppel样因子家族的成员是转录因子，在调节细胞分化和激活方面发挥重要作用。我们鉴定了这个家族的一个成员，称为KLF4，它在体内与心脏移植损伤相关的巨噬细胞中高表达。KLF4的表达与干扰素-γ诱导活化的巨噬细胞有关，而在抗炎生长因子转化生长因子-β1(TGF-β1)的作用下KLF4的表达降低。KLF4在巨噬细胞中过表达可有效诱导iNOS等巨噬细胞活化标志物，并抑制转化生长因子-β1介导的效应。这些观察结果使我们得出了一个中心假设，即KLF4是巨噬细胞激活和TAA的关键调节因子。在本建议的第一部分，我们探讨了KLF4的S抑制转化生长因子-β1信号转导的机制。在AIM2中，我们检测了KLF4诱导巨噬细胞iNOS基因表达的能力。最后，在AIMS中，我们评估了KLF4过表达对TAA发生和巨噬细胞效应功能的影响。这些研究将为KLF4在调节巨噬细胞激活中的作用提供重要的见解。这些研究的结果具有相当大的科学价值，可以作为调节TAA和巨噬细胞对细胞因子刺激的反应的新治疗策略的基础。

DESCRIPTION (provided by applicant): Transplantation-associated arteriosclerosis (TAA) is the major cause of death in recipients who survive more than one year after cardiac transplantation. TAA is characterized by infiltration of inflammatory cells followed by the formation of a diffuse, concentric neointima in which smooth muscle cells and macrophages accumulate. Cells of the immune system-particularly the macrophage-plays a key role in TAA. Through elaboration of inflammatory cytokines, uptake of oxidized lipids, and release of proteolytic enzymes, activated macrophages are critical to TAA. As such, identification of factors that regulate macrophage activation is of critical importance. Members of the Kruppel-like family of factors are transcription factors which play important roles in regulating cell differentiation and activation. We identified a member of this family termed KLF4 whose expression is highly expressed in macrophages associated with heart transplant lesions in vivo. KLF4 expression correlates with the induction of activated macrophages in response to interferon-gamma and is decreased in response to the anti-inflammatory growth factor, transforming growth factor-betal (TGF-b1). KLF4 overexpression in macrophages potently induces markers of macrophage activation such as iNOS and inhibits effects mediated by TGF-b1. These observations have led us to the central hypothesis that KLF4 serves as a critical regulator of macrophage activation and TAA. In AIM1 of this proposal we explore the mechanistic basis for KLF4's ability to inhibit TGF-b1 signaling. In AIM2, we examine the ability of KLF4 to induce macrophage iNOS gene expression. Finally, in AIMS, we assess the consequences of KLF4 overexpression on the development of TAA and on macrophage effector functions. These studies will provide important insight regarding the role of KLF4 in regulating macrophage activation. The results of these studies are of considerable scientific interest and may serve as the basis for novel therapeutic strategies to modulate TAA and the macrophage response to cytokine stimulation.