Interleukin-21 promotes the development of ulcerative colitis and regulates the proliferation and secretion of follicular T helper cells in the colitides microenvironment

Abstract

Patients with ulcerative colitis (UC) are at increased risk of developing colitis-associated colon cancer. Previous studies have indicated that interleukin (IL)-21, which is predominantly secreted by follicular T helper (Tfh) cells, is overproduced in inflammatory bowel diseases. In order to investigate the role of IL-21 in UC and the association between IL-21 and Tfh cells, the number of Tfh cells and the level of IL-21 were investigated in colonic tissues from UC patients and wild-type (WT) mice, which were induced by dextran sulphate sodium (DSS). High Tfh cell counts and levels of IL-21 were observed in UC patients and WT mice with DSS-induced colitis. Subsequent comparison of the mucosal damage and expression of Tfh-associated cytokines in the WT mice and IL-21 knockout (IL-21KO) mice following DSS administration, revealed that IL-21KO mice were largely protected against colitis and exhibited reduced infiltration of Tfh cells, as well as decreased production of Tfh-associated cytokines. The present study also found that IL-21 was necessary for the proliferation and secretion of Tfh cells in vitro. In addition, neutralization of IL-21 in DSS-administered WT mice using anti-IL-21 reduced the number of Tfh cells and the level of mucosal damage. Administration of a neutralizing IL-21 antibody decreased the colonic infiltration of Tfh cells and reduced damage to the mucosa. These results indicated that Tfh cells are important in UC and that its effector molecule, IL-21, is not only a critical regulator of inflammation, but also regulates the proliferation and response of Tfh cells in the colitis microenvironment.