The IL-21 receptor augments Th2 effector function and alternative macrophage activation.
Pesce, John 1; Kaviratne, Mallika 1; Ramalingam, Thirumalai R. 1; Thompson, Robert W. 1; Urban, Joseph F. 2; Cheever, Allen W. 3; Young, Deborah A. 4; Collins, Mary 4; Grusby, Michael J. 5; Wynn, Thomas A. 1
[Article] Journal of Clinical Investigation. 116(7):2044-2055, July 2006.

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The IL-21 receptor (IL-21R) shows significant homology with the IL-4R, and CD4 Th2 cells are an important source of IL-21. Here we examined whether the IL-21R regulates the development of Th2 responses in vivo. To do this, we infected IL-21R-/- mice with the Th2-inducing pathogens Schistosoma mansoni and Nippostrongylus brasiliensis and examined the influence of IL-21R deficiency on the development of Th2-dependent pathology. We showed that granulomatous inflammation and liver fibrosis were significantly reduced in S. mansoni-infected IL-21R-/- mice and in IL-21R / mice treated with soluble IL-21R-Fc (sIL-21R-Fc). The impaired granulomatous response was also associated with a marked reduction in Th2 cytokine expression and function, as evidenced by the attenuated IL-4, IL-13, AMCase, Ym1, and FIZZ1 (also referred to as RELM[alpha]) responses in the tissues. A similarly impaired Th2 response was observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4R[alpha] and IL-13R[alpha]1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following stimulation with IL-4 and IL-13. As such, these data identify the IL-21R as an important amplifier of alternative macrophage activation. Collectively, these results illustrate an essential function for the IL-21R in the development of pathogen-induced Th2 responses, which may have relevance in therapies for both inflammatory and chronic fibrotic diseases.

Copyright (C) 2006 The American Society for Clinical Investigation, Inc.