Cooperation among Stat1, glucocorticoid receptor, and PU.1 in transcriptional activation of the high-affinity Fc gamma receptor I in monocytes

IFN-gamma and glucocorticoids regulate inflammatory and immune responses th rough Stat1 and glucocorticoid receptor (GR) transcription factors, respect ively, The biological responses to these polypeptides are determined by int egration of various signaling pathways in a cell-type and promoter-dependen t manner. In this study we have characterized the molecular basis for the f unctional cooperation between IFN-gamma and dexamethasone (Dex) in the indu ction of the high-affinity Fc gamma receptor I (Fc gamma RI) in monocytes. Dex did not affect IFN-gamma-induced Stat1 DNA binding activity or induce n ovel DNA-binding complexes to the Fc gamma RI promoter. By using cell syste ms lacking functional GR or Stat1, we showed that GR stimulated Stat1-depen dent transcription in a ligand-dependent manner, while Stat1 did not influe nce GR-dependent transcription. The cooperation required phosphorylation of Tyr(701), DNA binding, and the hans-activation domain of Stat1, but did no t involve Ser(727) phosphorylation of Stat1 or physical interaction between GR and Stat1, The costimulatory effect of Dex was not dependent on a conse nsus glucocorticoid response element in the Stat1-responsive promoters, but required the DNA-binding and trans-activation functions of GR, and Dex-ind uced protein synthesis. GR activated the natural Fc gamma RI promoter const ruct, and this response required both Stat1 and the Ets family transcriptio n factor PU.1. Previously, physical association between GR and Stat5 has be en shown to enhance Stat5-dependent and suppress GR-dependent transcription . The results shown here demonstrate a distinct, indirect mechanism of cros s-modulation between cytokine and steroid receptor signaling that integrate s Stat1 and GR pathways with cell type-specific PU.1 transcription factor i n the regulation of Fc gamma RI gene transcription.