Signaling pathways involved in CD44 regulation in human monocytic cells

CD44是一种存在于大多数细胞类型上的黏附分子，负责与结缔组织中存在的透明质酸结合。因此，CD44介导细胞-细胞和细胞-基质的相互作用，在炎症和肿瘤发展过程中的细胞迁移中发挥重要作用。大多数细胞表达CD44，但能与HA结合。某些炎性细胞因子如肿瘤坏死因子-α和内毒素如脂多糖可引起CD44结构的改变，使其与透明质酸结合，增加其细胞黏附。CD44与HA的黏附也可以导致某些分子/生长因子的产生，也被称为促炎细胞因子，它们是导致炎症的原因。因此，单核细胞通过CD44-HA相互作用与T细胞结合是一个关键的促炎事件，而单核细胞与HA结合能力的上调是其参与炎症反应的关键事件。本实验室和其他实验室的研究结果表明，内毒素和包括肿瘤坏死因子-α在内的几种促炎细胞因子可诱导人单核细胞CD44的表达和黏附表型的产生。因此，了解从非粘附型向粘附型转变的分子基础具有重要的生物学意义，值得对这一现象进行研究。因此，这项研究的总体目标是描述CD44表达调节和黏附CD44表型产生的分子机制。具体地说，我们将研究PI3和MAP等细胞内信号分子在肿瘤坏死因子-α和脂多糖刺激下单核细胞CD44表达和黏附CD44表型生成中的作用。这将通过研究第二信使的表达，包括MAP和酪氨酸激酶，以及各种转录因子和DNA结合蛋白的诱导，如EGR-1和AP-1来完成。

CD44 is a adhesion molecule present on most cell types and is responsible for binding to hyaluronic acid present in the connective tissue. Therefore, CD44 mediates cell-cell and cell-matrix interactions and plays an important role in cell migration during inflammation and cancer development. Most cells express CD44 but can bind HA. Certain inflammatory cytokines such as TNF-a and endotoxins such as lipopolysaccharides can cause modification in the structure of CD44 so that it can bind HA and increase their cell adhesion. Adhesion of CD44 with HA can also cause the production of certain molecules /growth factors, also called proinflammatory cytokines, which are responsible for causing inflammation. Therefore, binding of monocytes with T cells through CD44-HA interactions is a key pro-inflammatory event, and the upregulation of the ability of monocytes to bind HA is a key event in their participation in inflammatory responses. The results from our laboratory and others suggest that endotoxins (LPS), and several pro-inflammatory cytokines including TNF-a induce the expression of CD44 and generation of an adhesive phenotype in human monocytes. Therefore, understanding the molecular basis for the switch from a non-adhesive to adhesive phenotype has important biological consequences and merit investigation of this phenomenon. Therefore, the overall aim of this research proposal is to delineate the molecular mechanisms underlying the regulation of CD44 expression and generation of an adhesive CD44 phenotype. Specifically, we will study the role of intracellular signaling molecules such as PI3 kinase amd MAP kinases in the regulation of CD44 expression and generation of adhesive CD44 phenotype in monocytic cells following stimulation with TNF-alpha and LPS. This will be accomplished by investigating the expression of second messengers including the MAP and tyrosine kinases and the induction of various transcription factors and DNA binding proteins such as egr-1 and AP-1.