Glucocorticoid receptors are down-regulated in inflamed colonic mucosa but not in peripheral blood mononuclear cells from patients with inflammatory bowel disease.
BACKGROUND
Growing evidence indicates that the immune system and the hypothalamic-pituitary-adrenal system are linked by several mechanisms, for example intracellular glucocorticoid receptors (hGR). Glucocorticoids are the standard treatment of acute attacks of inflammatory bowel disease (IBD). Binding of glucocorticoids to hGR down-regulates the transcription of inflammatory genes that can propagate IBD.


METHODS
IBD patients were either treated with 5-60 mg of prednisolone for more than 1 week or were without glucocorticoid treatment for more than 4 weeks. hGR levels were determined from isolated cytosol of peripheral blood mononuclear cells (PBMCs) or mucosal biopsies using a radioassay with [3H]-dexamethasone. Interleukin (IL) 6 levels were determined by enzyme-linked immunosorbent assay (ELISA).


RESULTS
The systemic (PBMC) hGR levels of corticosteroid-treated IBD patients were significantly lower than those of control subjects (59.6 +/- 57.1 dpm mg-1 cytosol protein vs. 227.0 +/- 90.8 dpm mg-1 cytosol protein, P = 0.007) and IBD patients not receiving glucocorticoid treatment (179.7 +/- 171.3 dpm mg-1 cytosol protein, P = 0.002). Systemic hGR levels in untreated IBD patients did not differ significantly from those in control subjects. In patients with connective tissue diseases, systemic hGR levels were also found to be decreased in the absence of glucocorticoid treatment. Systemic hGR levels in patients with Crohn's disease (CD) treated with steroids (66.6 +/- 61.0 dpm mg-1 cytosol protein) were not different from those in patients with ulcerative colitis (UC) (56.1 +/- 51.6 dpm mg-1 cytosol protein). In contrast to these findings, mucosal hGR levels were significantly decreased in both steroid-treated (18.0 +/- 15.5) and not steroid-treated (37.8 +/- 30.5) patients compared with control subjects (125.6 +/- 97.1; P = 0.00009 and P = 0.0008 respectively). IL-6 levels in all IBD groups with and without steroids were significantly different from those in control subjects.


CONCLUSIONS
In IBD there is no difference in systemic hGR levels between not steroid-treated patients and control subjects, in spite of inflammatory activity (IL-6). Mucosal hGR levels were decreased independently of treatment, probably leading to a decreased protection against NF-kappaB action in the intestinal mucosa.
Rogler
G
G
Department of Internal Medicine I, University of Regensburg, Germany.
Meinel
A
A
Lingauer
A
A
Michl
J
J
Zietz
B
B
Gross
V
V
Lang
B
B
Andus
T
T
Schölmerich
J
J
Palitzsch
K D
KD
D001667:Binding, Competitive / Q000502:physiology; D002458:Cell Fractionation; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014316:Tritium
D005938:Glucocorticoids; D015850:Interleukin-6; D011965:Receptors, Glucocorticoid; D014316:Tritium; D003907:Dexamethasone