title: Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA. kopazdra@utmb.edu.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA. kopazdra@utmb.edu.
authors.forename: Konrad
authors.initials: K
authors.lastname: Pazdrak
authors.affiliation: Undergraduate Summer Research Program, University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Young
authors.initials: Y
authors.lastname: Moon
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.
authors.forename: Christof
authors.initials: C
authors.lastname: Straub
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurosky
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001249:Asthma / Q000188:drug therapy; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics*; D004804:Eosinophils; D006801:Humans; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D050976:Basic-Leucine Zipper Transcription Factors; C508599:IL5 protein, human; D015848:Interleukin-5; C497440:NFIL3 protein, human; D034741:RNA, Small Interfering; D003907:Dexamethasone; D051573:Proto-Oncogene Proteins c-pim-1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: Apoptosis; Eosinophils; Glucocorticoid receptor; Signal transduction