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, GRbeta, 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 GRbeta and GRalpha in hGR gene of CD patients. The aim of this study is to assess the expression of GRalpha and GRbeta 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 hGRalpha-mRNA in patients in remission was significantly lower than in controls (P < 0.05). The amount of hGRbeta-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 hGRbeta mRNA in GC-resistant patients with an active disease. High levels of hGRbeta 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 hGRbeta mRNA expression level in PBMC is connected with GC-resistance of CD patients.
Institute of Gastroenterology and Liver Diseases, Meir Hospital, Kfar Saba 4428, Israel.
R
R
Towers
T
T
Naftali
G
G
Gabay
M
M
Carlebach
A
A
Klein
B
B
Novis
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004351:Drug Resistance / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000097:blood* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D015415:Biomarkers; D005938:Glucocorticoids; D020382:Interleukin-18; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta