We propose to study the interactions between the proinflammatory cytokines TNF-alpha, IL-1beta and IFN-gamma, and the immunosuppressive cytokine TGF-beta in human glioma cells. We are interested in how these cytokines regulate expression of intercellular adhesion molecule-1 (ICAM- 1) in glioma cells. ICAM-1 is a cytokine-inducible adhesion molecule expressed by glioma cells in vivo, and is the physiologic ligand for the beta2 integrins LFA-1 and Mac-1. Cell adhesion mediated by ICAM-1 and LFA-1/Mac-1 is important for a functional immune system, and is critical for immune cell mediated cytotoxicity. ICAM-1 expression by glioma cells may influence activation of lymphocytes and macrophages/microglia via interactions with LFA-1 and Mac-1, respectively. These interactions can facilitate and enhance immune surveillance in the central nervous system, which is depressed in patients with gliomas. It is critical to understand how ICAM-1 is regulated in glioma cells, especially since these cells have evolved mechanisms which allow them to escape immune surveillance. We have demonstrated that ICAM-1 expression in glioma cells is upregulated by TNF-alpha, IL-1beta and IFN-gamma, and that TGF-beta inhibits ICAM-1 expression in a stimulus-specific manner, i.e., TNF- alpha/IL-1beta induced expression is inhibited, while IFN-gamma induced expression is not affected. We hypothesize that TGF-beta mediated downregulation of TNF-alpha/IL-1beta induced ICAM-1 expression allows glioma cells to escape immune surveillance, thereby resulting in tumor progression. We will determine how the ICAM-1 gene is regulated at the molecular level in glioma cells (Aim #1). Second, we will extend our studies on the intracellular signals involved in ICAM-1 expression, emphasizing the involvement of protein kinase C and tyrosine kinase activity (Aim #2). It is important to understand the second messengers utilized by glioma cells, as these intracellular mediators can serve as targets for therapeutic intervention. Third, we will examine he mechanism(s) by which TGF-beta inhibits ICAM-1 expression in glioma cells (Aim #3). Lastly, we will elucidate the functional significance of ICAM-1 expression by glioma cells (Aim #4). Studies will be performed to assess whether cytokine-induced ICAM-1 expression by glioma cells enhances their susceptibility to immune cell mediated cytotoxicity, and if TGF-beta blocks this process, allowing glioma cells to escape immune destruction. These studies will provide a comprehensive understanding of the molecular mechanisms by which ICAM-1 is regulated in glioma cells, and the functional significance of ICAM-1 expression.
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