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

Ling Bo Li, Elena Goleva, Clifton F. Hall, Liang Shiou Ou, Donald Y.M. Leung

Research output: Contribution to journalJournal Article peer-review

127 Scopus citations

Abstract

Microbial superantigens induce human T-cell resistance to corticosteroids. Understanding the molecular pathways resulting in corticosteroid-resistant T cells is important because this condition can complicate the treatment of inflammation. 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 α (GCRα) localization was defined on the basis of intracellular staining. Protein phosphorylation was measured by means of Western blotting. 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 GCRα directly in an in vitro kinase assay. Of note, superantigen-induced corticosteroid resistance was associated with abrogation of GCRα nuclear translocation. This effect could be reversed by treatment with MEK/ERK pathway inhibitors. 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 GCRα phosphorylation and inhibition of dexamethasone-induced GCRα nuclear translocation.

Original languageEnglish
Pages (from-to)1059-1069
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume114
Issue number5
DOIs
StatePublished - 11 2004
Externally publishedYes

Keywords

  • MEK/ERK pathway
  • Superantigens
  • T cells
  • corticosteroids
  • glucocorticoid receptor
  • steroid resistance

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