Journal ArticleDOI
81. IFN-alpha and IL-6 reduce glucocorticoid sensitivity in murine microglia: A role for FKBP5?
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TLDR
IFN-α and IL-6 induce GC resistance in microglia and it is hypothesised that IFN- α-induced increases in FKBP5 result in GR being held in the cytosol thereby preventing GC signalling.Abstract:
Dysregulation of the GC system permitting excessive inflammation in the presence of elevated GCs occurs in depression, and is thought to be due to impaired GC signalling. We propose FKBP5, which acts to reduce GR activation, has a role in GC dysregulation. Glucocorticoid induced leucine zipper (GILZ) is a GC-inducible gene that is used as a readout of GR activation. The current objective was to examine the ability of IFN-α, IL-6, TNF-α, and IL-1β to impact GC sensitivity in microglia. These cytokines were chosen due to their implication in depression. The ability of these cytokines to alter mRNA expression of GR, FKBP5 and GILZ under basal conditions and in response to dexamethasone (DEX) in BV2 microglia was examined. Both IL-6 and IFN-α attenuated DEX-induced increases of GILZ, indicating the presence of GC resistance. IFN-α increased basal expression of FKBP5 and consistent with its negative feedback function attenuated DEX-induced FKBP5 expression. IL-6 did not alter basal expression of GR, FKBP5 or GILZ, but did attenuate the DEX-induced increases of FKBP5 and GILZ. Immunofluorescent staining shows that IFN-αand IL-6 reduce the degree of DEX-induced GR translocation and that IFN-α increased the co-localisation of GR and FKBP5. Taken together, IFN-α and IL-6 induce GC resistance in microglia and we hypothesise that IFN-α-induced increases in FKBP5 result in GR being held in the cytosol thereby preventing GC signalling.read more
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Journal ArticleDOI
Endogenous interleukin-6 amplifies interleukin-17 production and corticoid-resistance in peripheral T cells from patients with multiple sclerosis
Thais B. Ferreira,Joana Hygino,Priscila O. Barros,Bruna Teixeira,Taissa M. Kasahara,Ulisses C. Linhares,Lana M. Ferreira Lopes,Claudia Cristina Ferreira Vasconcelos,Regina Maria Papais Alvarenga,Ana Cristina Wing,Regis M. Andrade,Arnaldo F.B. Andrade,Cleonice A.M. Bento +12 more
TL;DR: The results suggest that IL‐6 might be involved in MS pathogenesis by enhancing IL‐17 production and reducing corticoid inhibitory effects on activated T cells.
Journal ArticleDOI
GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology.
Angeline Sharmila Thiagarajah,Laura Eades,Prabakar Rajan Thomas,Emma Kathryn Guymer,Eric F Morand,David M Clarke,Michelle Theresa Leech +6 more
TL;DR: In this review, glucocorticoid-induced leucine zipper (GILZ), a product of GR-initiated gene transcription, will be discussed in the context of GR dysfunction in psychopathology.