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IFN- Reverses IL-2– and IL-4–Mediated T-Cell Steroid Resistance

¹ Division of Pediatric Allergy and Immunology, National Jewish Health; and ² Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Donald Leung, Ph.D., National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206. E-mail: leungd{at}njhealth.org

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-; 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)- nuclear translocation in both CD4⁺ and CD8⁺ T cells. The presence of IL-4 significantly down-regulated IFN- production by IL-2–stimulated cells. Importantly, addition of IFN- to the IL-2/IL-4 combination restored GCR 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-–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- inhibited p38 MAPK phosphorylation and enhanced GCR nuclear translocation in response to DEX. These data indicate that combination IL-2/IL-4 inhibits GCR nuclear translocation in human T cells, and this effect is reversed by IFN- via inhibition of p38 MAPK activation.

Key Words: T cells • cytokines • glucocorticoid receptor • steroid resistance • p38 MAPK

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