High levels of glucocorticoid receptors in patients with active Crohn's disease may predict steroid resistance

Up to 20% of Crohn's disease (CD) patients respond poorly to glucocorticoids (GC). A product of an alternative splicing of the glucocorticoid receptor (GR) premRNA, GR beta, may play a role as a dominant inhibitor of the glucocorticoid response. Increasing evidence suggests that inflammatory cytokines such as interleukin (IL)-18 alternate the splicing of the primary transcript between the two isoforms GR beta and GR alpha in hGR gene of CD patients. The aim of this study is to assess the expression of GR alpha and GR beta in patients with CD and to look for a possible correlation between these receptors and the response to glucocorticoid treatment. Forty-two CD patients and 17 healthy volunteers were studied. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed using real-time PCR techniques. Serum IL-18 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). The amount of hGR alpha-mRNA in patients in remission was significantly lower than in controls (P < 0.05). The amount of hGR beta-mRNA was significantly higher in GC-resistant patients in the active stage of disease compared with all other groups (P < 0.05). Patients in the active stage of the disease had higher levels of IL-18 than patients in remission and both had higher levels than controls (P < 0.05). The amounts of IL-18 were directly correlated with the amount of hGR beta mRNA in GC-resistant patients with an active disease. High levels of hGR beta might be connected to GC resistance. IL-18 might participate in the alternative splicing of the hGR preliminary mRNA of CD patients. The results support the theory that augmented hGR beta mRNA expression level in PBMC is connected with GC-resistance of CD patients.