ICAM-1 GENE EXPRESSION IN MALIGNANT GLIAL TUMORS

Project: Research project

Project Details

Description

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.
StatusNot started