BACKGROUND: In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon gamma (IFNgamma) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown. OBJECTIVE: To examine whether interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD. METHODS: Duodenal mucosal samples were taken from CD patients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNgamma was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CD patients. Finally, the role of IL21 in controlling T-bet and IFNgamma was also evaluated in cultures of biopsies taken from treated CD patients and cultured with a peptic-tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody. RESULTS: Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CD patients. Blockade of IL21 activity in biopsies of untreated CD patients reduced T-bet and IFNgamma secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNgamma induction. CONCLUSIONS: IL21 is overproduced in the mucosa of CD patients, where it helps sustain T-bet expression and IFNgamma production.
BACKGROUND: In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon gamma (IFNgamma) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown. OBJECTIVE: To examine whether interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD. METHODS: Duodenal mucosal samples were taken from CDpatients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNgamma was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CDpatients. Finally, the role of IL21 in controlling T-bet and IFNgamma was also evaluated in cultures of biopsies taken from treated CDpatients and cultured with a peptic-tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody. RESULTS: Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CDpatients. Blockade of IL21 activity in biopsies of untreated CDpatients reduced T-bet and IFNgamma secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNgamma induction. CONCLUSIONS:IL21 is overproduced in the mucosa of CDpatients, where it helps sustain T-bet expression and IFNgamma production.
Authors: Hugh James Freeman; Angeli Chopra; Michael Tom Clandinin; Alan Br Thomson Journal: World J Gastroenterol Date: 2011-05-14 Impact factor: 5.742
Authors: Daniela De Nitto; Ivan Monteleone; Eleonora Franzè; Francesco Pallone; Giovanni Monteleone Journal: World J Gastroenterol Date: 2009-10-07 Impact factor: 5.742
Authors: Yongjing Guo; Andrew A Hill; Renee C Ramsey; Frederick W Immermann; Christopher Corcoran; Deborah Young; Edward R Lavallie; Mark Ryan; Theresa Bechard; Richard Pfeifer; Garvin Warner; Marcia Bologna; Laird Bloom; Margot O'Toole Journal: J Transl Med Date: 2010-05-26 Impact factor: 5.531