The role of Ets-1 in mast cell granulocyte-macrophage colony-stimulating factor expression and activation.
Ets-1 is a transcription factor with restricted expression in lymphocytes, 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 study that Ets-1 is also expressed in some mast cells constitutively and can be induced in primary mast cells with stimuli that activate mast cells. We also show that Ets-1 plays a role in the regulation of granulocyte-macrophage CSF (GM-CSF), a cytokine expressed by activated mast cells. We have characterized a murine growth factor-independent mast cell line, FMP6-, derived from a factor-dependent cell line, FMP1.6. FMP6- 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, and the down-regulation of IL-4. The parental FMP1.6 cell line displays a mucosal mast cell-like phenotype. FMP6- cells have increased Ets-1 expression and achieve growth-factor independence by the autocrine production of GM-CSF and IL-3. Transient transfection of an Ets-1 expression construct in FMP6- cells results in 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 demonstrates 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 activation, and because of the central role of mast cells in inflammatory processes, such as asthma and rheumatoid arthritis, they identify Ets-1 as potentially contributing to the pathophysiology of such diseases.
Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Melbourne, Australia.
L H
LH
McKinlay
M J
MJ
Tymms
R S
RS
Thomas
A
A
Seth
S
S
Hasthorpe
P J
PJ
Hertzog
I
I
Kola
D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor