Selective gene regulation by glucocorticoid receptor translational isoforms in T cells. (46.10)

Abstract

Abstract Glucocorticoids are indispensable in treating inflammatory diseases including asthma and hay fever. The antiinflammatory actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). We previously found that alternative translation mechanisms produce multiple GR isoforms. To determine the functions of the translational isoforms of GR, we generated clones of Jurkat T cell lines expressing individual GR isoforms. Microarray analysis indicated that GR isoforms have unique gene targets. Realtime RT-PCR experiments confirmed that some genes are regulated by the GR-C but not by the GR-A isoform. These genes have a wide range of physiologic functions in T cell differentiation (eomesodermin, EOMES; and phosphoinositide-3-kinase interacting protein 1, PIK3IP1), proliferation (tumor necrosis factor superfamily member 8, TNFSF8, and B-cell translocation gene 1, BTG1), cell adhesion (junctional adhesion molecule 3, JAM3), virus-killing (interferon stimulated exonuclease gene 20kDa, ISG20), NF-B signaling (5-azacytidine induced 2, AZI2), and transcription regulation (runt-related transcription factor 2, RUNX2). Furthermore, we found that mitogens induced the GR-C but not other GR isoforms in purified CD3+ cells. Thus, GR-C selective genes may mediate glucocorticoid actions in activated T cells. These genes may also serve as biomarkers for selective GR isoform activation and provide new targets for the development of novel anti-inflammatory agents.