IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance.

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.

[1]  M. Garabedian,et al.  Modulation of glucocorticoid receptor phosphorylation and transcriptional activity by a C-terminal-associated protein phosphatase. , 2007, Molecular endocrinology.

[2]  C. Dominguez,et al.  High-Content Screening Analysis of the p38 Pathway: Profiling of Structurally Related p38α Kinase Inhibitors Using Cell-Based Assays , 2006 .

[3]  D. Leung,et al.  Divergent expression and function of glucocorticoid receptor β in human monocytes and T cells , 2006, Journal of leukocyte biology.

[4]  Richard J Martin,et al.  Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. , 2006, American journal of respiratory and critical care medicine.

[5]  I. Adcock,et al.  Update on glucocorticoid action and resistance. , 2006, The Journal of allergy and clinical immunology.

[6]  High-content screening analysis of the p38 pathway: profiling of structurally related p38alpha kinase inhibitors using cell-based assays. , 2006, Assay and drug development technologies.

[7]  J. Cidlowski,et al.  Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. , 2005, The New England journal of medicine.

[8]  G. Chrousos,et al.  Intracellular Glucocorticoid Signaling: A Formerly Simple System Turns Stochastic , 2005, Science's STKE.

[9]  J. Cidlowski,et al.  The human glucocorticoid receptor: One gene, multiple proteins and diverse responses , 2005, Steroids.

[10]  L. Ou,et al.  Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. , 2004, The Journal of allergy and clinical immunology.

[11]  Z. Szatmáry,et al.  Inhibition of Glucocorticoid Receptor-mediated Transcriptional Activation by p38 Mitogen-activated Protein (MAP) Kinase* , 2004, Journal of Biological Chemistry.

[12]  M. Garabedian,et al.  Modulation of Glucocorticoid Receptor Function via Phosphorylation , 2004, Annals of the New York Academy of Sciences.

[13]  J. Travers,et al.  Cytokine Milieu of Atopic Dermatitis, as Compared to Psoriasis, Skin Prevents Induction of Innate Immune Response Genes 1 , 2003, The Journal of Immunology.

[14]  K. Kisich,et al.  A Role for STAT5 in the Pathogenesis of IL-2-Induced Glucocorticoid Resistance1 , 2002, The Journal of Immunology.

[15]  M. Garabedian,et al.  Deciphering the Phosphorylation “Code” of the Glucocorticoid Receptor in Vivo * 210 , 2002, The Journal of Biological Chemistry.

[16]  I. Adcock,et al.  p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. , 2002, The Journal of allergy and clinical immunology.

[17]  E. Silverman,et al.  Heterogeneity of therapeutic responses in asthma. , 2000, British medical bulletin.

[18]  Paludan.  Interleukin‐4 and Interferon‐γ: The Quintessence of a Mutual Antagonistic Relationship , 1998, Scandinavian journal of immunology.

[19]  M. Garabedian,et al.  Phosphorylation and Inhibition of Rat Glucocorticoid Receptor Transcriptional Activation by Glycogen Synthase Kinase-3 (GSK-3) , 1998, The Journal of Biological Chemistry.

[20]  Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor , 1997, Molecular and cellular biology.

[21]  S. Szefler,et al.  Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. , 1997, American journal of respiratory and critical care medicine.

[22]  S. Szefler,et al.  Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation. , 1995, American journal of respiratory and critical care medicine.

[23]  R. Martin,et al.  Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma , 1995, The Journal of experimental medicine.

[24]  S. Szefler,et al.  Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. , 1994, The Journal of clinical investigation.

[25]  S. Szefler,et al.  Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. , 1993, Journal of immunology.

[26]  M. Garabedian,et al.  Protein phosphatase types 1 and/or 2A regulate nucleocytoplasmic shuttling of glucocorticoid receptors. , 1991, Molecular endocrinology.