Moodie, F.M.; Noble, J.; Satsangi, J.; Seckl, J.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA54
Academic Journal
Background: Recent studies suggest that altered tissue sensitivity to glucocorticoids may underlie steroid insensitivity in patients with Ulcerative Colitis (UC). The expression of mdrla, GR, MR and 11βHSD2 (a key enzyme in the inactivation of circulating glucocorticosteroids-GCs) along a healthy colon and the effect of altered levels of GCs on these key targets has not been studied in detail. Methods: Wistar rats were either adrenalectomised (ADX), sham operated or had no surgery, and injected daily for one week with either dexamethasone (dex) (200ug/kg) or vehicle (2.5% et/OH). Rats were sacrificed, colons removed, sectioned and snap-frozen. Radioactive in situ hybridisation was used to analyse mRNA distribution of the above genes in colonic epithelial cells (ECs). Results: The expression of mdr1a mRNA was increased in the proximal colon compared to the distal colon (p<0.001), especially within the upper crypts. Dex treatment decreased mdrl a mRNA in all ECs. After ADX, mdr1a expression was increased in the upper crypt ECs (p<0.001). Both GR and MR increased after ADX (p<0.001), although dex treatment only reduced GR mRNA levels (p<0.05). 11βHSD2 mRNA was highest in ECs in the upper crypts compared to the base of the crypts (p<0.01), however in the distal colon all ECs expressed high levels. After ADX 11βHSD2 mRNA increased both within cells in the crypt axis and along the co]on. Conclusion: Expression of mdr1a and 11βHSD2 varies within the crypt axis and along the colon, in contrast to GR and MR. In particular GC excess down-regulation of GR may reduce steroid sensitivity, but this is set against dex-induced reduction in MDR and 11βHSD2 which favours GC. GCs influence colonic expression of these genes, and may directly influence the efficacy of steroids in the treatment of UC.


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