title: IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance.
abstract: Corticosteroids are the most common therapeutic approach for control of tissue inflammation. Combination IL-2/IL-4 is known to induce T-cell steroid resistance. This can be reversed with IFN-gamma; however, the mechanism by which this occurs is unknown. In the current study, we found that treatment of peripheral blood mononuclear cells with combination IL-2/IL-4 for 48 hours, but not with IL-2 or IL-4 alone, abrogated dexamethasone (DEX)-induced glucocorticoid receptor (GCR)-alpha nuclear translocation in both CD4(+) and CD8(+) T cells. The presence of IL-4 significantly down-regulated IFN-gamma production by IL-2-stimulated cells. Importantly, addition of IFN-gamma to the IL-2/IL-4 combination restored GCRalpha nuclear translocation in response to DEX. Furthermore, DEX-induced mitogen-activated protein kinase (MAPK) phosphatase-1 induction, used as a readout for corticosteroid-induced transactivation, was significantly greater (P < 0.05) in media and IL-2/IL-4/IFN-gamma-treated conditions compared with IL-2/IL-4-treated cells. The combination of IL-2/IL-4 induced p38 MAPK activation in CD3(+) cells (30.5 +/- 5.7% cells expressed phospho-p38 MAPK versus no phospho-p38 MAPK expression after media treatment). The presence of the p38 MAPK inhibitor, SB203580, or IFN-gamma inhibited p38 MAPK phosphorylation and enhanced GCRalpha nuclear translocation in response to DEX. These data indicate that combination IL-2/IL-4 inhibits GCRalpha nuclear translocation in human T cells, and this effect is reversed by IFN-gamma via inhibition of p38 MAPK activation.
authors.affiliation: National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Li
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D004351:Drug Resistance / Q000187:drug effects*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; C508594:IL2 protein, human; C508598:IL4 protein, human; D007093:Imidazoles; D007376:Interleukin-2; D011725:Pyridines; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D015847:Interleukin-4; D003907:Dexamethasone; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C093642:SB 203580
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