Glucocorticoid receptor mRNA in patients with ulcerative colitis: a study of responders and nonresponders to glucocorticosteroid therapy.
OBJECTIVE
Up to 30% of patients with severe-to-moderate attacks of ulcerative colitis (UC) respond poorly to glucocorticosteroid (GCS) treatment. The reason for this unresponsiveness is unknown.


OBJECTIVE
Our aim was to evaluate possible differences in glucocorticoid receptor (GR) density in peripheral leukocytes and effects of low-dose GCS treatment on GR density and on the hypothalamic-pituitary-adrenal axis in UC patients who had received high-dose GCS treatment due to a moderate or severe attack. Eleven UC patients in remission who were responders (Rs) to previous GCS treatment were compared with 10 patients who failed GCS therapy and had a colectomy (nonresponders. NRs). Ten healthy individuals served as controls.


METHODS
Quantitation of GR mRNA by a solution hybridization assay in peripheral leukocytes and a low-dose adrenocorticotropin hormone stimulation test was performed before and after low-dose dexamethasone (DEX) treatment for 14 days. The glucocorticoid-responsive gene for metallothionein IIa (MTIIa) was also analyzed by a solution hybridization assay in peripheral leukocytes.


RESULTS
Overall, basal GR mRNA levels were higher in patients than in controls (p < 0.0001). There were no significant differences between NRs and Rs. None of the groups down-regulated their GR mRNA levels in response to DEX treatment. Basal and stimulated cortisol levels decreased significantly only among NRs after DEX (p = 0.012 and 0.0093). MTIIa levels were lower in NRs as compared with Rs, both in mononuclear (p = 0.0059) and in polynuclear leukocytes (p = 0.030).


CONCLUSIONS
Patients with UC in remission exhibit higher levels of GR mRNA in peripheral leukocytes. We speculate that this may be secondary to an underlying up-regulation of proinflammatory factors also present in patients in clinical remission. Differences in GR mRNA levels per se thus may not be important for the ability of patients with UC to respond to GCS treatment. The hypothalamic pituitary adrenal axis was suppressed by low-dose DEX treatment only in NRs, possibly indicating that steroid-resistance is not a generalized phenomenon. Lower levels of MTIIa in NRs may indicate a diminished efficiency of GR regulation in steroid-refractory patients.
Flood
L
L
Department of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital and Novum, Stockholm, Sweden. lars.flood@gastro.hs.sll.se
Löfberg
R
R
Stierna
P
P
Wikström
A C
AC
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D003082:Colectomy; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000097:blood; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D008668:Metallothionein