THE ROLE OF ETS-1 IN MAST-CELL GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR EXPRESSION AND ACTIVATION

Ets-1 is a transcription fatter with restricted expression in lymphocy tes, and it has been implicated in the regulation of T cell genes such as TCR alpha, TCR beta, CD4, IL-2, and TNF-alpha. We show in this stu dy that Ets-1 is also expressed in some mast cells constitutively and can he induced in primary mast cells with stimuli that activate mast c ells. We also show that Ets-l plays a role in the regulation of granul ocyte-macrophage CSF (GM-CSF), a cytokine expressed by activated mast cells. We have characterized a murine growth factor-independent mast c ell line, FMP6-, derived from a factor-dependent cell line, FMP1,6, FM P6- has acquired a distinct connective tissue mast cell-like phenotype , as characterized by the expression of mast cell proteases MMCP-4 and MMCP-6, expression of IL-12, anal the down-regulation of IL-4. The pa rental FMP1.6 cell line displays a mucosal mast cell-like phenotype. F MP6- cells have increased Ets-l expression and achieve growth-factor i ndependence by the autocrine production of GM-CSF and IL-3. Transient transfection of an Ets-l expression construct in FMP6- cells results i n transactivation of a GM-CSF reporter, while a point mutation in the consensus Ets binding site in the conserved lymphokine element, CLE0, abolishes Ets-1 transactivation, Importantly, antisense Ets-1 demonstr ates an ability to repress the activity of the GM-CSF reporter. These data suggest a role for Ets-1 in mast cell growth regulation and activ ation, and because of the central role of mast cells in inflammatory p rocesses, such as asthma and rheumatoid arthritis, they identify Ets-l as potentially contributing to the pathophysiology of such diseases.