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NFκB and glucocorticoid receptor activity in steroid resistance

Dawson, Charlotte, Dhanda, Ashwin, Conway-Campbell, Becky, DiMambro, Alexandra, Lightman, Stafford and Dayan, Colin Mark 2012. NFκB and glucocorticoid receptor activity in steroid resistance. Journal of Receptors and Signal Transduction 32 (1) , pp. 29-35. 10.3109/10799893.2011.641977

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Abstract

Resistance to the anti-inflammatory and immunosuppressive effects of steroids is an important clinical problem that complicates the treatment of approximately 30% of patients with conditions for which steroids are normally first-line therapy. Previous studies have shown that steroid-resistant (SR) patients have more severe disease and higher levels of inflammatory cytokine production than steroid-sensitive (SS) patients, but the molecular mechanisms for this remain poorly understood. Peripheral blood mononuclear cells from healthy volunteers were tested for steroid resistance by their in vitro response to the anti-proliferative effects of dexamethasone. The SR cohort had high baseline levels of NFκB DNA binding activity, equivalent to that in phytohemagglutinin (PHA)-stimulated SS cells. In SR cells, dexamethasone exposure, but not PHA, increased binding of the p65 NFκB subunit to the κB promoter element. Glucocorticoid receptor (GR) was not detected at either the κB promoter element or the glucocorticoid response element (GRE), suggesting that it does not translocate to the nucleus in these cells. Conversely, in SS cells, baseline p65 DNA binding activity was low and significantly increased by PHA, but not by dexamethasone. Unlike in SR cells, GR was detected at the κB element and at the GRE. These findings suggest that in SR patients, steroids may be harmful by increasing NFκB activity which would exacerbate disease by increasing transcription of inflammatory cytokines.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: p65 NFκB subunit, κB promoter element, glucocorticoid response element, peripheral blood mononuclear cell, inflammatory cytokine
Publisher: Informa Healthcare
ISSN: 1079-9893
Last Modified: 04 Jun 2017 03:54
URI: http://orca.cf.ac.uk/id/eprint/28960

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