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 - 24/08/11
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Denver, Colo, and Taoyuan, Taiwan
Abstract |
Background |
Microbial superantigens induce human T-cell resistance to corticosteroids.
Objective |
Understanding the molecular pathways resulting in corticosteroid-resistant T cells is important because this condition can complicate the treatment of inflammation.
Methods |
The response of human PBMCs to steroids was assessed by using proliferation assays after stimulation with superantigens or anti-CD3 in the presence of various kinase inhibitors. Glucocorticoid receptor ⍺ (GCR⍺) localization was defined on the basis of intracellular staining. Protein phosphorylation was measured by means of Western blotting.
Results |
In the current study we found that PBMCs stimulated with superantigen, but not anti-CD3, induced corticosteroid-resistant T cells. However, the purified T cells stimulated either with staphylococcal enterotoxin B (SEB) or anti-CD3 are susceptible to corticosteroid inhibition. These results imply that signals on antigen-presenting cells might act in concert with the T-cell receptor to cause steroid resistance. Blockade of CD40–CD40 ligand interaction had no effect on superantigen-induced corticosteroid resistance. However, CD28 costimulation with T-cell receptor activation induced corticosteroid resistance of human T cells in a dose-dependent manner. Superantigen stimulation, compared with anti-CD3 stimulation, was found to induce a more rapid and sustained phosphorylation of mitogen-activated extracellular signal-regulated kinase (ERK). Treatment with PD98059 and UO126 (specific mitogen-activated protein kinase kinase [MEK]/ERK inhibitors), but not a p38 inhibitor or a c-Jun N-terminal kinase inhibitor, restored the response to steroids, as indicated by proliferation assays. Furthermore, purified ERK1 and ERK2 were able to phosphorylate recombinant human GCR⍺ directly in an in vitro kinase assay. Of note, superantigen-induced corticosteroid resistance was associated with abrogation of GCR⍺ nuclear translocation. This effect could be reversed by treatment with MEK/ERK pathway inhibitors.
Conclusions |
These data are compatible with the hypothesis that superantigen-induced corticosteroid resistance involves the Raf-MEK-ERK1/ERK2 pathway of T-cell receptor signaling, which leads to GCR⍺ phosphorylation and inhibition of dexamethasone-induced GCR⍺ nuclear translocation.
Le texte complet de cet article est disponible en PDF.Key words : Superantigens, T cells, steroid resistance, MEK/ERK pathway, corticosteroids, glucocorticoid receptor
Abbreviations used : APC, CD40L, CR, Cy3, DAPI, ERK, GCR, IC50, JNK, MAPK, MEK, MFI, PI3K, PKC, SEB, TCR, TSST-1
Plan
Dr Leung's work was supported in part by National Institutes of Health grants HL36577, AR41256, and HL37260; the Ann and Louis Rudolph Kawasaki Disease Research Fund; and the Edelstein Family Chair in Pediatric Allergy and Immunology, the University of Colorado Cancer Center. |
Vol 114 - N° 5
P. 1059-1069 - novembre 2004 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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