Differential regulation of interleukin-17 and interferon- production in inflammatory bowel disease

Laura Rovedatti ¹, Takahiro Kudo ¹, Paolo Biancheri ¹, Massimiliano Sarra ², Charles Knowles ¹, David S Rampton ¹, Gino R Corazza ³, Giovanni Monteleone ², Antonio Di Sabatino ^3* and Thomas T MacDonald ¹

¹ Institute of Cell and Molecular Science, Barts and the London School of Medicine, London, United Kingdom
² Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy
³ First Department of Medicine, S. Matteo Hospital, University of Pavia, Pavia, Italy

^* To whom correspondence should be addressed. E-mail: a.disabatino{at}smatteo.pv.it.

Accepted 23 June 2009

Abstract

Background and aims: Interleukin (IL)-17 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 IBD patients (38 with Crohn’s disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL-17 and interferon (IFN)- were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL-12, IL-23, IL-1 plus IL-6, transforming growth factor (TGF)-1, or anti-IL-21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.

Results: IL-17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFN-. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL-17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in IBD patients than controls. IL-23 and IL-1 plus IL-6 had no effect on IBD LPMC production of IL-17, however IL-12 markedly increased IFN- production and decreased IL-17 production. TGF-1 dose-dependently decreased IFN-, but had no significant inhibitory effect on IL-17 production. Blocking IL-21 significantly down-regulated IL-17 production.

Conclusions: Our findings support a role for IL-12, TGF- and IL-21 in modulating IL-17/IFN- production in IBD. The abundant IL-17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFN-antibodies in clinical trials of Crohn’s disease.