Glucocorticoid sensitivity in inflammatory bowel disease

Figures & data

Table I. Synthetic glucocorticoids employed in the treatment of inflammatory bowel disease, adapted from Rang et al. (8).

		Relative potency in clinical use
Compound	Relative affinity for glucocorticoid receptor^a	Anti-inflammatory	Sodium-retaining	Duration of action after oral dose (hours)
Hydrocortisone	1	1	1	short (8–12)
Prednisolone	2.2	4	0.8	short (8–12)
Methylprednisolone	11.9	5	minimal	intermediate
Dexamethasone	7.1	30	minimal	long
Budesonide^b	195	nd	nd	very short (24.5)

^aHuman foetal lung cells.

^bEdsbacker and Andersson (9).

Figure 1. The structure of the glucocorticoid receptor (GR). A: The GR gene consists of at least nine alternative exon 1s (A–J) and eight other exons (2–9). The polymorphisms of the GR are presented at their respective positions in the gene. B: The alternative mRNA transcripts of the GR gene. The 13 different exon 1 splice variants do not alter the amino acid sequence of the gene. For GRα the presence of the different translation initiation sites for A-D3 isoforms is schematically presented. Arg = arginine. C: The full-length GRα, its main functional domains, and the sites of post-translational covalent modifications: S = sumoylation; Ub = ubiquitination.

Table II. Studies assessing the number and affinity of glucocorticoid receptors (GR) in colonic mucosa and peripheral blood mononuclear cells (PBMC) in inflammatory bowel disease.

Ref.	Objective	Patients, disease	Method	Results
(45)	To study the number of GR and their affinity to ligand in PBMC	11 UC	Whole cell [^3H]Dex- binding assay	Steroid non-responders (n = 6) had higher number of GR binding sites than responders (n = 5) or controls and lower affinity of GR to ligand than responders.
(40)	To study GR receptor numbers in PBMC and colonic mucosa	31 CD; 18 UC	Cytosolic [^3H]Dex-radioassay	Mucosal GR levels were decreased in IBD patients when compared with controls. In steroid-treated IBD patients GR numbers were lower in PBMC.
(44)	To investigate the expression of GR and the apparent dissociation constants in PBMC of IBD patients	22 UC; 17 CD	Whole cell [^3H]Dex-binding assay	In IBD patients the Kd was constantly higher than in the healthy controls. IBD patients not on steroid therapy had higher GR levels than steroid-treated IBD patients or controls.
(41)	To study GR mRNA levels in peripheral leucocytes and the effect of low-dose Dex treatment on them	21 UC	Quantitation of GR mRNA in solution hybridization assay	GR mRNA levels were higher in IBD patients than in the controls. The mRNA levels were the same between steroid responders (11) and non-responders (10).
(42)	To study GR mRNA expression in PBMC and colonic mucosa of IBD patients and whether they correlate with disease activity or can predict GC treatment response	33 UC; 21 CD	Quantitation of GR mRNA by RT-PCR, immunohistochemistry	Systemic and local GR mRNA expression was similar to controls; however, in the mucosa of UC patients with impaired GC response the levels were down-regulated. GR immunoreactivity was found in immune and epithelial cells.

Dex = dexamethasone; UC = ulcerative colitis; CD = Crohn's disease.

Table III. Studies assessing the association between the number of glucocorticoid receptors (GR) GRα and GRβ in peripheral blood mononuclear cells (PBMC) and colonic mucosa, and the response to glucocorticoid (GC) therapy in adult patients with inflammatory bowel disease.

Ref.	Objective	Patients, disease	Method	Results
(47)	To study whether RT-PCR analysis of hGRβ mRNA in PBMC of UC patients can predict the response to GC therapy	23 UC	GRα and GRβ analysis by mRNA RT-PCR, Western blot	GRβ was positive in 83.3% of the GC non-responders (n = 12) and in 9.1% of the GC-responsive patients (n = 11).
(48)	To quantify the levels and serial changes of PBMC GR mRNA in IBD patients	34 UC; 13 CD	Real-time fluorescence-monitored PCR	GRβ mRNA expression was increased in active UC. GRβ mRNA expression was also higher in GC-resistant than GC-sensitive UC.
(53)	To quantify the levels of GR mRNA in PBMC	17 CD	RT-PCR	GRα and GRβ mRNA levels were lower in patients with CD than in the controls. The longer the disease duration, the smaller the amount of GRα mRNA in PBMCs of the patients.
(49)	To study the expression of GRα and GRβ in colonic mucosal cells and their correlation with response to GC therapy and inflammation	25 UC	Immunohistochemistry	The expression of GRα was positively associated with response to GC treatment, whereas GRβ associated negatively with the response to GCs.
(50)	To assess the expression of GRα and GRβ in PBMCs of CD patients and to study their relationship to the response to GC therapy	42 CD	RT-PCR using real-time PCR techniques; IL-18 levels were measured with ELISA	GRβ mRNA expression was significantly higher in GC non-responders with active CD. In these patients, GRβ mRNA correlated directly with IL-18 levels measured from the serum.
(52)	To study whether GRβ expression in PBMCs of IBD patients could serve as a predictor of GC response	86 IBD	RT-PCR	GRβ expression was similar between GC-treated and non-GC-treated patients and between GC-responders and non-responders.
(51)	To study the relationship between the frequency and type of infiltrating cells expressing GRα, GRβ, and FOXP3 in biopsied colonic mucosa and the GC responsiveness of UC patients	38 UC	Immunohistochemistry, RT-PCR	GC non-responders had higher GRβ^+ cell count than GC-responders. The FOXP3^+ cell count was significantly higher in GC-responders.

UC = ulcerative colitis; CD = Crohn's disease.

Table IV. Other methods employed to study the glucocorticoid (GC) response in patients with inflammatory bowel disease (IBD).

Ref.	Objective	Patients, disease	Method	Results
(69)	To study the hypothesis that GC-resistant UC patients have GC-resistant T lymphocytes	18 UC	Phytohaemagglutin-stimulated peripheral blood T lymphocytes treated with dexamethasone	Treatment failures and incomplete responders had an Imax of less than 60%; all complete responders had an Imax of more than 60%.
(70)	To compare the corticosensitivity of CD patients to that of healthy subjects	19 CD	Dexamethasone inhibition of LPS-induced cytokine secretion by whole blood cell cultures	CD patients had a markedly decreased dexamethasone-mediated inhibition of TNF-α secretion.
(71)	To study the lymphocytes in the colonic mucosa	30 UC; 15 CD	Immunohistochemistry, flow cytometry	High labelling of CD19^+ Ki-67 lymphocytes was specific for active UC that was resistant to GC therapy.
(72)	To study the relationship between steroid responsiveness and SLC22A4/A5 polymorphism located within IBD 5 locus	94 UC; 94 CD	Genotyping and haplotype analysis	The G allele on –368T > G in SLC22A5 was associated with steroid resistance in CD patients. Haplotype analysis between –446C > T and –368T > G in the SLC22A5 promoter region indicated CG allele as the risk haplotype for steroid resistance in CD patients.
(57)	To assess circulating GC bioactivity in paediatric patients with IBD	18 UC; 3 CD; 1 IC	Cell culture bioassay	The circulating GC bioactivity did not associate with clinical response to steroid therapy.
(60)	To evaluate whether white adipose-derived adiponectin and leptin could associate with the response to systemic GC therapy	16 UC; 2 CD; 1 IC	ELISA	High serum adiponectin associated with early appearing glucocorticoid-related side-effects.
(61)	To analyse the effect of GC-treated patient serum on the immune activation of healthy donor PBMC	16 UC; 2 CD; 1 IC	ELISA, RT-PCR	The expression of FOXP3 and GITR and the secretion of IFN-γ mirroring effector T cells decreased during glucocorticoid therapy.

UC = ulcerative colitis; CD = Crohn's disease; IC = indeterminate colitis; PBMC = peripheral blood mononuclear cells.

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