FKBP51 modulates steroid sensitivity and NFκB signalling: A novel anti‐inflammatory drug target. Issue 11 (14th September 2018)

• Record Type: Journal Article
• Authors: Kästle, Marc; Kistler, Barbara; Lamla, Thorsten; Bretschneider, Tom; Lamb, David; Nicklin, Paul; Wyatt, David
• Is Part Of: European journal of immunology. Volume 48:Issue 11(2018)
• Page Start: 1904
• Page End: 1914
• Publication Date: 2018-09-14
• Subjects: FKBP51 -- glucocorticoid receptor -- IKK -- NFκB -- steroid sensitivity; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201847699
• Languages: English
• ISSNs: 0014-2980

Abstract

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 expression, cytokine and chemokine secretion. In conclusion, we demonstrate that FKBP51 has the potential to control inflammation in steroid insensitive patients in a steroid‐dependent and independent manner and thus may be worthy of further study as a drug target. Abstract : FKBP51 can interact with the glucocorticoid receptor (GR) and the IKK complex. By decreasing the steroid affinity of the GR and facilitating the complex formation of IKKα, IKKβ, IKKγ, FKBP51 can modulate steroid efficacy and NFκB driven inflammation, which makes it an interesting target for steroid refractory diseases.