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

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.

FKBP Ligands—Where We Are and Where to Go?

“…Inspired by the well-established role of FKBP51 as a suppressor of the glucocorticoid receptor as well as its involvement in the nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) pathway, a research group from Boehringer Ingelheim recently explored the role of FKBP51 in models of glucocorticoid-resistant asthma (Kastle et al, 2018). Mice overexpressing FKBP51 in airway epithelial cells were resistant to low dose of glucocorticoids.…”

Glucocorticoid receptor mutations and clinical sensitivity to glucocorticoid in Chinese multiple sclerosis patients

“…The degree of dexamethasone-induced expression of FKBP51 in PBMC served as a marker for the clinical response to glucocorticoids in patients with asthma or rheumatoid arthritis [ 21 , 22 ]. Currently, investigations are undergoing on the application of FKBP51 in drug development [ 23 – 25 ]. Inhibitor of FKBP5 may enhance GC sensitivity and serve as a new drug for GC-resistant patients with acute MS attack.…”

The Many Faces of FKBP51

“…Indeed, no changes on a number of GR target genes could be detected in this study [32], pointing towards additional substrates of FKBP51 downstream of GR and FKBP51. Local viral overexpression of FKBP51 in airway epithelial cells reduced glucocorticoid responsiveness in an asthma model in mice, suggesting FKBP51 reduction as an anti-inflammatory (co)-treatment option for glucocorticoid-resistant asthma [43]. Importantly, no overt potentially adverse effects have been observed in FKBP51 −/− mice so far [44], suggesting FKBP51 to be a safe drug target.…”

“…FKBP51 was described as a regulator of NF-κB (nuclear factor binding near the κ light-chain in B-cells) signaling in different cell types. For this reason, FKBP51 has been suggested as a drug target for the treatment of NF-κB-mediated inflammation and cancer [43,83,84,85,86,87]. Nuclear factor-κB is a family of transcription factors affecting multiple cellular processes such as inflammation, proliferation, maturation, differentiation, survival, and apoptosis [88,89,90].…”