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

Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kB and the glucocorticoid receptor (GR). The human glucocorticoid receptor (hGR) gene encodes two protein isoforms: a cytoplasmic alpha form (GRa), which binds hormone, translocates to the nucleus, and regulates gene transcription, and a nuclear localized beta isoform (GRb), which does not bind known ligands and attenuates GRa action. We report here the identification of a tumor necrosis factor (TNF)responsive NF-kB DNA binding site 5* to the hGR promoter that leads to a 1.5-fold increase in GRa mRNA and a 2.0-fold increase in GRb mRNA in HeLaS3 cells, which endogenously express both GR isoforms. However, TNF-a treatment disproportionately increased the steady-state levels of the GRb protein isoform over GRa, making GRb the predominant endogenous receptor isoform. Similar results were observed following treatment of human CEMC7 lymphoid cells with TNF-a or IL-1. The increase in GRb protein expression correlated with the development of glucocorticoid resistance.