The regulation of glucocorticoid metabolism in Inflammatory Bowel Disease
M Hussey, A Cannon, G Holleran, C Kiat, B Hall, J O'Sullivan, M Sherlock, D McNamara
Department of Gastroenterology, Tallaght Hospital, Trinity Academic Gastroenterology Group
The 11 beta hydroxysteroid dehdrogenase (11βHSD) enzyme system has been previously shown to play a role in glucocorticoid metabolism in Inflammatory Bowel Disease (IBD). However the role of potential key regulators including hexose-6- phosphate dehydrogenase (H6PDH) & the Glucocorticoid Receptor alpha (GR-α) is unknown.
To examine the relative expression of 11βHSD enzyme regulators H6PDH and GR-α in an IBD cohort.
Frozen biobank samples from prospectively recruited IBD patients and controls which were previously examined for 11βHSD 1 & 2 expression were identified. Demographic and clinical data including CRP, clinical (Harvey-Bradshaw Index / Mayo Score), endoscopic & histological activity were recorded. Biopsies were analysed in batches using Quantitative real time RTPCR (TaqMan) using comercially available GR-α and H6PDH probes. Relative transcript levels were determined using 18S as a reference gene. Relative expression of GR-α and H6PDH were calculated as a mean and compared among groups and controlled for activity using a student t test, p value of ?0.05 was considered significant.
To date 24 IBD (12 Crohn’s, 12 UC) & 12 control subjects have been recruited. IBD & control cohorts were demographically similar with 50% (n= 12) versus 75% (n=9) female, mean age 42years (17-66 years) versus 57 years (19-83 years) respectively. Overall 50% (n=12) had mildly, 29% (n=7) moderately & 21% (n=5) severely active disease. The mean HBI was 6 (0-21), mean mayo score was 7(0-12)and mean CRP was 22mg/l (1-192.5mg/l). For active patients the mean CRP was 37mg/l versus 2.0mg/l for inactive disease, p<0.04 95% CI 68.8- 1.7. Overall between IBD patients and controls there was no difference in GR-? expression (4.5 au versus 2.1au (p=0.4), H6PDH expression 3.4au versus 3.9au (p=0.2) and 11?HSD-1 expression 416au versus 166au (p=0.4). In addition there was no statistical difference in GR-?, H6PDH or 11?HSD-1 expression within the IBD cohort based on either disease subtype, histological or biochemical activity. Interestingly, there was a significant difference in 11?HSD-2 expression between IBD patients (13.8 au) and controls (318.4 au), P<0.01 95%CI -517.5- - 91.7. As a result there was an increased proportion of 11?HSD-1 expression compared wth 11?HSD-2 in IBD patients versus controls 81:1 versus 1.5:1, P<0.006, 95% CI 57.7 – 78.5.
Expression of 11βHSD-1 and its regulator H6PDH do not vary in IBD. While GR-α receptor are levels are consistent, 11βHSD-2 down regulation and enhanced tissue cortisol bioavailability may play a central role in response to inflammation in patients with active IBD.