DIFFERENTIAL REGULATION OF INTERLEUKIN-17 AND INTERFERON-GAMMA PRODUCTION IN INFLAMMATORY BOWEL DISEASE

Abstract

BACKGROUND AND AIMS: Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still unclear. METHODS: Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn's disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon gamma (IFNgamma) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1beta plus IL6, transforming growth factor beta1 (TGFbeta1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells. RESULTS: IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNgamma. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNgamma production and decreased IL17 production. TGFbeta1 dose-dependently decreased IFNgamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production. CONCLUSIONS: Our findings support a role for IL12, TGFbeta and IL21 in modulating IL17/IFNgamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNgamma antibodies in clinical trials of Crohn's disease.