Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease

Table 1 Factors involved in glucocorticoid resistance

GR	Reduced GR mRNA expression[42]
	Reduced GC binding affinity[43]
	Polymorphisms in the NR3C1 gene[45]
GR heterocomplex	Altered expression of the chaperones and co-chaperones that make up the heterocomplex[74-78]
	Polymorphisms in the Hsp90 gene[79]
	Genetic variations in the STIP1 gene coding for Hop[79]
Nuclear transport factors	Polymorphisms in the Importin 13 gene[86]
Transcription machinery	Lower expression of SMARCB1 in resistant leukaemia cells[97]
Pro-inflammatory mediators	Polymorphisms in the NALP1 gene[72]
	TNF-α promoter SNP correlated with steroid response in several disease[149-154]
	IL-10 polymorphisms related with a positive prednisone response in children with ALL[159]
P-gp	Hyperexpression of P-gp in lymphocytes and epithelial cells from GC-resistant IBD patients[167]

GR: Glucocorticoid receptor; GC: Glucocorticoid; Hsp: Heat-shock protein; Hop: Hsp70/Hsp90 organization protein; P-gp: P-glycoprotein; NR3C1: Nuclear receptor subfamily 3, group C, member 1; NALP1: NACHT leucine-rich-repeat protein 1; SNP: Single nucleotide polymorphism; TNF-α: Tumor necrosis factor α; IL: Interleukin; ALL: Acute lymphoblastic leukemia; IBD: Inflammatory bowel disease.

Table 2 Factors involved in glucocorticoid resistance in inflammatory bowel disease

GR	Significantly lower expression of GR mRNA in the intestinal mucosa in patients with GC-resistant IBD[42]
	In colonic biopsies of UC patients, significantly more GRβ positive cells in the resistant group than in the GC sensitive control group[60]
	Significantly higher frequency of BclI polymorphism in GC-responsive IBD patients[61]
Pro-inflammatory mediators	TNF-α G-308A polymorphism significantly associated with steroid resistance and requirement for surgery[152]
	Association between this polymorphism and steroid dependency in a large population of CD patients[155]
	Higher probability of non-response to GCs in pediatric IBD patients carriers of the NALP1 variant genotype[72]
P-gp	Hyperexpression of P-gp in circulating lymphocytes and epithelial cells from patients with GC resistant IBD[167]
	Association between GC refractory CD and P-gp intronic polymorphisms[173]
	C3435T polymorphism in pediatric IBD Italian patients treated with GC not associated with response to therapy[152]

GR: Glucocorticoid receptor; GC: Glucocorticoid; UC: Ulcerative colitis; IBD: Inflammatory bowel disease; TNF-α: Tumor necrosis factor α; NALP1: NACHT leucine-rich-repeat protein 1; P-gp: P-glycoprotein; CD: Crohn’s disease.