Signaling pathways involved in CD44 regulation in human monocytic cells

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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.