Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3

Konrad Pazdrak, Young Moon, Christof Straub, Susan Stafford, Alexander Kurosky

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    The mainstay of asthma therapy, glucocorticoids (GCs) exert their therapeutic effects through the inhibition of inflammatory signaling and induction of eosinophil apoptosis. However, laboratory and clinical observations of GC-resistant asthma suggest that GCs' effects on eosinophil viability may depend on the state of eosinophil activation. In the present study we demonstrate that eosinophils stimulated with IL-5 show impaired pro-apoptotic response to GCs. We sought to determine the contribution of GC-mediated transactivating (TA) and transrepressing (TR) pathways in modulation of activated eosinophils' response to GC by comparing their response to the selective GC receptor (GR) agonist Compound A (CpdA) devoid of TA activity to that upon treatment with Dexamethasone (Dex). IL-5-activated eosinophils showed contrasting responses to CpdA and Dex, as IL-5-treated eosinophils showed no increase in apoptosis compared to cells treated with Dex alone, while CpdA elicited an apoptotic response regardless of IL-5 stimulation. Proteomic analysis revealed that both Nuclear Factor IL-3 (NFIL3) and Map Kinase Phosphatase 1 (MKP1) were inducible by IL-5 and enhanced by Dex; however, CpdA had no effect on NFIL3 and MKP1 expression. We found that inhibiting NFIL3 with specific siRNA or by blocking the IL-5-inducible Pim-1 kinase abrogated the protective effect of IL-5 on Dex-induced apoptosis, indicating crosstalk between IL-5 anti-apoptotic pathways and GR-mediated TA signaling occurring via the NFIL3 molecule. Collectively, these results indicate that (1) GCs' TA pathway may support eosinophil viability in IL-5-stimulated cells through synergistic upregulation of NFIL3; and (2) functional inhibition of IL-5 signaling (anti-Pim1) or the use of selective GR agonists that don't upregulate NFIL3 may be effective strategies for the restoring pro-apoptotic effect of GCs on IL-5-activated eosinophils.

    Original languageEnglish (US)
    Pages (from-to)421-431
    Number of pages11
    JournalApoptosis
    Volume21
    Issue number4
    DOIs
    StatePublished - Apr 1 2016

    Fingerprint

    Interleukin-3
    Interleukin-5
    Eosinophils
    Glucocorticoids
    Transcription Factors
    Apoptosis
    Dexamethasone
    Dual Specificity Phosphatase 1
    Proto-Oncogene Proteins c-pim-1
    Glucocorticoid Receptor Deficiency
    Up-Regulation
    Asthma
    Glucocorticoid Receptors
    Therapeutic Uses
    Crosstalk
    Proteomics
    Small Interfering RNA
    Interleukin-2
    Chemical activation
    Modulation

    Keywords

    • Apoptosis
    • Eosinophils
    • Glucocorticoid receptor
    • Signal transduction

    ASJC Scopus subject areas

    • Cell Biology
    • Clinical Biochemistry
    • Biochemistry, medical
    • Cancer Research
    • Pharmaceutical Science
    • Pharmacology

    Cite this

    Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3. / Pazdrak, Konrad; Moon, Young; Straub, Christof; Stafford, Susan; Kurosky, Alexander.

    In: Apoptosis, Vol. 21, No. 4, 01.04.2016, p. 421-431.

    Research output: Contribution to journalArticle

    Pazdrak, Konrad ; Moon, Young ; Straub, Christof ; Stafford, Susan ; Kurosky, Alexander. / Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3. In: Apoptosis. 2016 ; Vol. 21, No. 4. pp. 421-431.
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