Cytokines alter glucocorticoid receptor phosphorylation in airway cells: Role of phosphatases

Belaid Bouazza, Kateryna Krytska, Manel Debba-Pavard, Yassine Amrani, Richard E. Honkanen, Jennifer Tran, Omar Tliba

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Corticosteroid insensitivity (CSI) represents a profound challenge in managing patients with asthma. We recently demonstrated that short exposure of airway smooth muscle cells (ASMCs) to proasthmatic cytokines drastically reduced their responsiveness to glucocorticoids (GCs), an effect that was partially mediated via interferon regulatory factor-1, suggesting the involvement of additional mechanisms (Am J Respir Cell Mol Biol 2008;38:463-472). Although GC receptor (GR) can be phosphorylated at multiple serines in the Nterminal region, the major phosphorylation sites critical for GR transcriptional activity are serines 211 (Ser211) and 226 (Ser226). We tested the novel hypothesis that cytokine-induced CSI in ASMCs is due to an impaired GR phosphorylation. Cells were treated with TNF-α (10 ng/ml) and IFN-g (500 UI/ml) for 6 hours and/or fluticasone (100 nm) added 2 hours before. GR was constitutively phosphorylated at Ser226 but not at Ser211 residues. Cytokines dramatically suppressed fluticasone-induced phosphorylation of GR on Ser211 but not on Ser226 residues while increasing the expression of Ser/Thr protein phosphatase (PP)5 but not that of PP1 or PP2A. Transfection studies using a reporter construct containing GC responsive elements showed that the specific small interfering RNA-induced mRNA knockdown of PP5, but not that of PP1 or PP2A, partially prevented the cytokine suppressive effects on GR-meditated transactivation activity. Similarly, cytokines failed to inhibit GC-induced GR-Ser211 phosphorylation when expression of PP5 wassuppressed.Wepropose that the novelmechanismthat proasthmatic cytokine-inducedCSI inASMCsis due, in part, to PP5-mediated impairment of GR-Ser211 phosphorylation.

Original languageEnglish (US)
Pages (from-to)464-473
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number4
DOIs
StatePublished - Oct 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • Airway remodeling
  • Airway smooth muscle
  • Asthma
  • Corticosteroid insensitivity
  • Serine/threonine protein phosphatase

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