FKBP51 modulates steroid sensitivity and NFκB signalling: A novel anti-inflammatory drug target

European Journal of Immunology
Marc KästleDavid Wyatt

Abstract

Steroid refractory inflammation is an unmet medical need in the management of inflammatory diseases. Thus, mechanisms, improving steroid sensitivity and simultaneously decreasing inflammation have potential therapeutic utility. The FK506-binding protein 51 (FKBP51) is reported to influence steroid sensitivity in mental disorders. Moreover, biochemical data highlight a connection between FKBP51 and the IKK complex. The aim of this study was to elucidate whether FKBP51 inhibition had utility in modulating steroid resistant inflammation by increasing the sensitivity of the glucocorticoid receptor (GR) signalling and simultaneously inhibiting NFκB-driven inflammation. We have demonstrated that FKBP51 silencing in a bronchial epithelial cell line resulted in a 10-fold increased potency for dexamethasone towards IL1beta-induced IL6 and IL8, whilst FKBP51 over-expression of FKBP51 reduced significantly the prednisolone sensitivity in a murine HDM-driven pulmonary inflammation model. Immunoprecipitation experiments with anti-FKBP51 antibodies, confirmed the presence of FKBP51 in a complex comprising Hsp90, GR and members of the IKK family. FKBP51 silencing reduced NFκB (p50/p65) nucleus translocation, resulting in reduced ICAM expressi...Continue Reading

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Citations

Jan 24, 2019·Biomolecules·Andreas HähleFelix Hausch
Dec 21, 2018·Frontiers in Pharmacology·Jürgen M KolosFelix Hausch
Apr 12, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Tian SongXinghu Zhang
Jan 19, 2021·Advances in Medical Sciences·Zhixiu XiaYong Feng
Apr 10, 2021·Biochemistry. Biokhimii︠a︡·Alexey P BolshakovNatalia V Gulyaeva

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Methods Mentioned

BETA
ubiquitination
PMA
nuclear translocation
lavage
transfection
ELISA
biopsies
genetic modifications
FCS
PCR

Software Mentioned

MASCOT

Related Concepts

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