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

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