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Title: The Unique Functions of the Type-II IL-4 Receptor are revealed in IL-13R¿1-deficient mice

item PESCE, J
item SHEIKH, F
item WILSON, M
item MURPHY, A
item Urban, Joseph
item WYNN, T

Submitted to: Nature Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2007
Publication Date: 1/9/2008
Citation: Ramalingam, T.R., Pesce, J.T., Sheikh, F., Cheever, A.W., Mentink-Kane, M.M, Wilson, M.S., Stevens, S., Valenzuela, D.M., Murphy, A.J., Yancopoulos,G.D., Urban Jr, J.F., Donnelly, R.P.,Wynn, T.A. 2008. Unique functions of the type-II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha 1 chain. Nature Immunology. (1):25-33.

Interpretive Summary: Helminth (worm) parasites affect the host immune response similar to allergens that induce hyper secretion of mucus, airway hyper reactivity, and re-structuring of the tissues. These components of the host responses are essentially side effects of the effort to eliminate parasites but become annoying when induced by allergens. Control of these side effects could be useful in limiting the expression of disease. The current study shows that the absence of the major receptor for IL-13, which is highly expressed during allergic responses, can eliminate many of the harmful side effects of an allergic response. Loss of the receptor increases susceptibility to parasitic infection, but is inconsequential when parasites are not present. The information is important to researchers that study the control of infectious diseases in humans and livestock, and the relationship between parasitic infection and allergic disease.

Technical Abstract: The IL-4 receptor is a central mediator of Th2-mediated diseases and associates with either the common gamma chain (type-I IL-4R) or IL-13Ra1 (type-II IL-4R) to form two receptor complexes. Here, using IL-13Ra1-/- mice, we characterized the distinct functions of the type-II IL-4R. In contrast to IL-4Ra-/- mice, that display weak Th2 response, IL-13Ra1-/- mice developed Th2 responses stronger than WT. Nevertheless, they displayed significantly reduced fibrosis and mortality following S. mansoni infection and markedly increased susceptibility to N. brasiliensis. The IL-13Ra1 also controlled allergen-induced airway hyper reactivity and mucus hyper secretion but not alternative-macrophage activation or arginase-1 expression, for which the type-I IL-4R was sufficient. Hence therapeutics that selectively target the type-II IL-4R might prove the best strategy to regulate Th2-driven disease.