Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2005
Publication Date: 7/3/2005
Citation: Pesce, J., Kaviratne, M., Ramalingam, T., Thompson, R.W., Urban Jr, J.F., Cheever, A., Young, D., Collins, M., Grusby, M., Wynn, T. 2006. The IL-21 receptor auguments Th2 effector function and alternative macrophage activation. Journal of Clinical Investigation. 116(7):2044-2055. Interpretive Summary: Parasitic helminth infections and allergen-induced hypersensitivity initiate the expression of a pattern of protein messenger molecules or cytokines that activate local allergic disease. Expression of these molecules in the intestine can have profound immediate effects on nutrient absorption and metabolism, and long term effects on tissue fibrosis and remodeling that generally affect intestinal function. We have characterized the induction of cytokines IL-4 and IL-13 during parasitic infection and their interaction with their receptors on immune cells and intestinal tissues. Local expression of IL-4 and IL-13 can affect smooth muscle contractility and epithelial secretion and absorption via receptors expressed on selected cell types. The recently characterized IL-21 cytokine and its receptor have structural similarity to IL-4 and it is hypothesized to affect the response to parasitic infection. We have demonstrated that IL-21 levels are increased during parasitic worm infection and can affect the development of fibrotic responses in the liver and lung as the parasites invades. It remains to be determined if IL-12 induction can also affect intestinal responses to infection and regulate nutrient uptake and metabolism. These results place IL-21 into a family of cytokines that regulate allergic disease and tissue remodeling and will help to determine if strategies to control the expression of IL-21 can improve lung, liver and intestinal function without negatively affecting the elimination of the infection. This work is important to scientists that study the interaction between infectious disease and appropriate immune function.
Technical Abstract: The IL-21 receptor (R) shows significant homology with the IL-4R. CD4+ Th2 cells can also produce IL-21. Here, we examine the impact of IL-21R-deficiency following infection with the TH2-inducing pathogens Schistosoma mansoni and Nippostrongylus brasiliensis. We show that granulomatous inflammation and liver fibrosis are significantly reduced in S. mansoni-infected IL-21R-/- mice. The impaired granulomatous response was associated with a marked reduction in type-2 cytokine expression and function, as evidenced by the attenuated IL-4, IL-13, AMCase, Ym1, and FIZZ1/RELMalpha responses in the tissues. A similarly impaired type-2 response was also observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4Ralpha and IL-13Ralpha1 expression in macrophages, resulting in increased FIZZ1 and Arginase-1 expression following stimulation with IL-4 and IL-13. Thus, IL-21 signaling promotes alternative macrophage activation, which contributes to the development of chronic TH2-mediated inflammation and fibrosis.