A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance.
Glucocorticoids (GC) are highly effective in the control of diseases associated with T cell activation. However, a subset of individuals is GC insensitive. Previous studies have demonstrated that IL-2 can induce steroid resistance in mouse T cells. However, the mechanism for this phenomenon is unknown. In the current study we found that the murine cell line (HT-2) is steroid resistant when incubated with IL-2, but steroid sensitive when grown in IL-4. Furthermore, when HT-2 cells are treated with IL-2, the glucocorticoid receptor (GCR) does not translocate to the cell nucleus after dexamethasone treatment. In contrast, the GCR in IL-4-stimulated HT-2 cells does translocate into the cell nucleus after dexamethasone treatment. IL-2-induced steroid insensitivity in HT-2 cells appears to be a signaling event as the effects of IL-2 on nuclear translocation of the GCR occurred within 30 min even in the presence of cycloheximide. Indeed, preincubation of HT-2 cells with a Janus-associated kinase 3 inhibitor restored nuclear translocation of the GCR even in the presence of IL-2. Immunoprecipitation experiments revealed that phosphorylated STAT5 and GCR formed immune complexes. This association may lead to retardation of GCR nuclear translocation because IL-2 was not able to induce steroid insensitivity in splenocytes from STAT5 knockout mice. This study demonstrates a novel role for STAT5 in IL-2-induced steroid insensitivity.
Goleva
Elena
E
Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Kisich
Kevin O
KO
Leung
Donald Y M
DY
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D019281:Dimerization; D004351:Drug Resistance / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D053616:Janus Kinase 3; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008894:Milk Proteins; D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3