What Did the Researchers Do and Find?
Transcription factors have to move into the nucleus of cells (so-called nuclear translocation) to control the expression of their target genes, so the researchers first asked whether fluticasone affects the cellular localization of GATA-3. Fluticasone treatment of activated T lymphocytes growing in dishes, they report, inhibited the nuclear translocation of GATA-3 and reduced Th2 cytokine expression. Other experiments showed that the inhibition of GATA-3 nuclear translocation was partly caused by competition between the glucocorticoid receptor bound to fluticasone and GATA-3 for binding to importin-α, a protein that is required for nuclear import. However, fluticasone also prevented the nuclear translocation of GATA-3 in a second way. Before GATA-3 can bind to importin-α, phosphate groups have to be added to specific sites in GATA-3. This “phosphorylation” requires an enzyme called p38 MAP kinase, and the researchers found that fluticasone treatment of activated T lymphocytes induced the expression of MAP kinase phophatase-1, a p38 MAP kinase inhibitor. Finally, when the researchers treated seven patients with mild asthma with inhaled fluticasone, they found that fluticasone also inhibited GATA-3 nuclear translocation in the lymphocytes circulating in the patients' blood.