Generalised Glucocorticoid Resistance

Generalised Glucocorticoid Resistance

Charmandari Evangelia, Chrousos George P, Kino Tomoshige
US Endocrinology - Volume 4 - Issue II European Endocrinology - Volume 4 - Issue II
Published: February 2009
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Figure 4b: Interaction Between NF-κB and Activated Glucocorticoid Receptor



On the other hand, NF-κB can repress the transcriptional activity of hGRα. In a regulated response, GC-hGRα activation is sufficient to maintain NF-κB levels in homeostasis and achieve a reduction in transcription of inflammatory mediators over time. Studies that examined the activities of GC-hGRα and NF-κB in patients with systemic inflammation and acute respiratory distress syndrome (ARDS) showed that those who improved on treatment with moderate doses of glucocorticoids had an excess activation of GC-hGRα compared to NFκB, as evidenced by the increased GC-hGRα binding to NF-κB and increased nuclear GC-hGRα binding (GC-hGRα-driven response). On the other hand, non-improvers demonstrated an excess of NF-κB activation compared with GC-hGRα, leading to protracted transcription of inflammatory mediators over time. In non-improvers, GC-hGRα binding to NF-κB was modestly increased, while nuclear NF-κB binding to its respective response elements increased substantially over time and nuclear GC-hGRα and cytoplasmic IκBα levels declined (NF-κBdriven response).79,80

Further studies that assessed the activity of NF-κB in biopsy specimens from steroid-resistant and steroid-sensitive patients with severe Crohn’s disease (CD) and UC showed that NF-κB activation was mainly noted in lamina propria macrophages in steroid-sensitive patients and in epithelial cells in steroid-resistant patients.81 Similar were the findings related to the activation of AP-1 and the upstream kinases p38 and JNK.82 The functional interference of these pro-inflammatory mediators with the glucocorticoid response was supported by reporter gene assays, which demonstrated that NF-κB, JNK and p38 inhibited the transcriptional activity of hGRα. These findings suggest that the generalised glucocorticoid resistance documented in patients with systemic inflammation, CD and UC is associated with constitutive activation of NF-κB and stress-activated protein kinases, which may inhibit the anti-inflammatory action of a limited number of hGRα molecules by reducing the transcriptional activity of hGRα.

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