6th Annual BMRP Investigator Meeting - Abstract
Interleukin-21 (IL-21) Triggers Inflammatory Signals in the Gut. Relevance for Human Inflammatory Bowel Diseases.
Giovanni Monteleonea, Massimo Fantinib
Department of Internal Medicine, University Tor Vergata of Rome (Italy)
A loss of tolerance towards the bacterial microflora probably causes both Crohn´s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). The abnormal activation of the immune system in the gut of IBD patients is characterized by a cascade of cellular events orchestrated by cytokine crosstalk between immune and non-immune cells.
Department of Internal Medicine, University Tor Vergata of Rome (Italy)
A loss of tolerance towards the bacterial microflora probably causes both Crohn´s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). The abnormal activation of the immune system in the gut of IBD patients is characterized by a cascade of cellular events orchestrated by cytokine crosstalk between immune and non-immune cells.
IL-21, the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade in the gut. IL-21 is highly expressed in both CD and UC tissue, where it is supposed to promote the recruitment of T cell from the blood into the inflamed intestine and facilitate the secretion of matrix degrading enzymes by fibroblasts. In CD, IL-21 also sustains the ongoing Th1-mediated immune response. Up-regulation of IL-21 is not however a specific hallmark of IBD, because it is also produced in excess in the gut of patients with celiac disease and in the stomach of patients with Helicobacter pylori infection as compared with controls. Enhanced production of IL-21 was also found in the colon of mice with experimental colitis. Molecular analysis of IL-21 biological effects revealed that IL-21 prevents the TGF-beta-dependent expression of FoxP3, the master control of Tregs commitment, and the induction of suppressive capacity in naïve CD4+ T cells, while promoting the differentiation of Th17 cells, a novel class of effector cells implicated in inflammation in many tissues. In vivo, CD4+ naïve T cells activated in the presence of TGF-beta and IL-21 failed to suppress colitis induced by CD4+ T cells. In contrast, CD4+ T cells activated in the presence of IL-21 induced a pronounced inflammatory response characterized by high levels of IL-17 and RORgt, the transcription factor expressed by Th17 cells. Overall, there is now sufficient evidence to suggest that targeting IL-21 will be of therapeutic benefit in IBD.
aPrincipal Investigator; bCo-Investigator and Presenter