A comparison of in vitro bioassays to determine cellular glucocorticoid sensitivity

Abstract

An altered cellular glucocorticoid (GC) sensitivity is associated with several pathophysiological conditions such as asthma, diabetes, or rheumatoid arthritis. Several bioassays have been developed and employed to assess cellular GC sensitivity of peripheral blood mononuclear cells (PBMC), but correlations between these have rarely been investigated. We have compared four mitogen-based assays and an FK506 binding protein 51 (FKBP51) mRNA induction assay, using ten controls and a GCresistant patient. The mitogen-based assays were performed using either diluted wholeblood or isolated PBMC, and showed relatively large assay variations for the parameters maximal effect and half-maximal effect concentration. The FKBP51 assay showed smaller intra-assay and within-individual variation compared with the mitogen-based assays. The wholeblood-based mitogen assays and the FKBP51 assay clearly discriminated the GC-resistant patient from the controls but, in contrast to expectations, both PBMC-based mitogen assays did not. The GC-induced FKBP51 mRNA increase in PBMC may be an alternative to determine an altered individual GC sensitivity with several advantages as compared with mitogen-based assays, such as the use of unstimulated PBMC, and a better intra-and inter-individual reproducibility.

Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone

“…The glucocorticoid receptor co-chaperone FKBP51 (encoded by FKBP5) plays a pivotal role for glucocorticoid sensitivity (30). A common SNP in FKBP5 associates with frequency of depressive episodes and response to antidepressant therapy, and with risk of post-traumatic stress disorder in adults who had experienced childhood abuse (19,32,33); both conditions might relate to cerebral glucocorticoid sensitivity.…”

“…Variable levels of the co-chaperone FK506 binding protein (FKBP51; encoded by FKBP5) determines glucocorticoid sensitivity (30,31). The common SNP rs1360780 may be associated with increased sensitivity to glucocorticoids (19,32,33); hence we postulated increased risk of GIOP in carriers of this SNP.…”

Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

“…Moreover, FKBP51 is potently induced by corticosteroids (35,36), suggesting that FKBP51 may function in a negative-feedback loop to limit GR signaling within a permitted range. Indeed, FKBP51 overexpression may contribute to glucocorticoid resistance syndrome in primates (37,38), and FKBP51 mRNA expression levels in peripheral blood mononuclear cells may provide an assay for individual sensitivity to corticosteroids (39,40). In principle, FKBP51 expression might affect clinical responsiveness to corticosteroids in asthma.…”

Mechanisms of Reduced Glucocorticoid Sensitivity in Bronchial Asthma

“…FK506-binding protein 51 (FKBP51) expression might affect clinical responsiveness to GCs (Denny at al., 2005;Reynolds et al, 1999;Vermeer et al, 2004a;Vermeer et al, 2004b). FKBP51 is an immunophilin chaperone protein residing in the cytoplasm before GC binding.…”