Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform:: A mechanism for the generation of glucocorticoid resistance

Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kappaB and the glucocorticoid receptor (GR), The human glucocorticoid receptor (hGR) gene encodes two protein isoforms: a cytoplasmic alpha form (GR alpha), which binds hormone, translocates to the nucleus, and regulates gene transcription, and a nuclear localized beta isoform (GRP), which does not bind known ligands and attenuates GR alpha action. We report here the identification of a tumor necrosis factor (TNF)responsive NF-kappaB DNA binding site 5' to the hCR promoter that leads to a 1.5-fold increase in GR alpha mRNA and a 2.0-fold increase in GRP mRNA in HeLa53 cells, which endogenously express both GR isoforms, However, TNF-alpha treatment disproportionately increased the steady-state levels of the GR beta protein isoform over GR alpha, making GR beta the predominant endogenous receptor isoform, Similar results were observed following treatment of human CEMC7 lymphoid cells with TNF-alpha or IL-1, The increase in GRP protein expression correlated with the development of glucocorticoid resistance.