Abstract
The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2)–mediated disease and associates with either the common γ-chain to form the type I IL-4R or with the IL-13R α1 chain (IL-13Rα1) to form the type II IL-4R. Here we used Il13ra1−/− mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra−/− mice, which have weak TH2 responses, Il13ra1−/− mice had exacerbated TH2 responses. Il13ra1−/− mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Rα1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.
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References
Finkelman, F.D. et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139–155 (2004).
Padilla, J. et al. IL-13 regulates the immune response to inhaled antigens. J. Immunol. 174, 8097–8105 (2005).
Grunig, G. et al. Roles of interleukin-13 and interferon-γ in lung inflammation. Chest 121, 88S (2002).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Chiaramonte, M.G., Donaldson, D.D., Cheever, A.W. & Wynn, T.A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).
Wynn, T.A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).
Murata, T., Taguchi, J., Puri, R.K. & Mohri, H. Sharing of receptor subunits and signal transduction pathway between the IL-4 and IL-13 receptor system. Int. J. Hematol. 69, 13–20 (1999).
Chiaramonte, M.G. et al. Regulation and function of the interleukin 13 receptor α2 during a T helper cell type 2-dominant immune response. J. Exp. Med. 197, 687–701 (2003).
Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R.K. & Kitani, A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat. Med. 12, 99–106 (2006).
Valenzuela, D.M. et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat. Biotechnol. 21, 652–659 (2003).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Richter, A. et al. The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am. J. Respir. Cell Mol. Biol. 25, 385–391 (2001).
Wang, I.M., Lin, H., Goldman, S.J. & Kobayashi, M. STAT-1 is activated by IL-4 and IL-13 in multiple cell types. Mol. Immunol. 41, 873–884 (2004).
Doucet, C., Giron-Michel, J., Canonica, G.W. & Azzarone, B. Human lung myofibroblasts as effectors of the inflammatory process: the common receptor γ chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-α. Eur. J. Immunol. 32, 2437–2449 (2002).
Lordan, J.L. et al. Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J. Immunol. 169, 407–414 (2002).
Zurawski, G. & de Vries, J.E. Interleukin 13 elicits a subset of the activities of its close relative interleukin 4. Stem Cells 12, 169–174 (1994).
Lai, Y.H. & Mosmann, T.R. Mouse IL-13 enhances antibody production in vivo and acts directly on B cells in vitro to increase survival and hence antibody production. J. Immunol. 162, 78–87 (1999).
Punnonen, J. & de Vries, J.E. IL-13 induces proliferation, Ig isotype switching, and Ig synthesis by immature human fetal B cells. J. Immunol. 152, 1094–1102 (1994).
Guo, L. et al. Disrupting Il13 impairs production of IL-4 specified by the linked allele. Nat. Immunol. 2, 461–466 (2001).
McKenzie, G.J. et al. Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9, 423–432 (1998).
McKenzie, A.N. et al. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc. Natl. Acad. Sci. USA 90, 3735–3739 (1993).
Li, L. et al. IL-4 utilizes an alternative receptor to drive apoptosis of Th1 cells and skews neonatal immunity toward Th2. Immunity 20, 429–440 (2004).
Hoffmann, K.F. et al. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions. FASEB J. 15, 2545–2547 (2001).
Brunet, L.R., Finkelman, F.D., Cheever, A.W., Kopf, M.A. & Pearce, E.J. IL-4 protects against TNF-α-mediated cachexia and death during acute schistosomiasis. J. Immunol. 159, 777–785 (1997).
Fallon, P.G., Richardson, E.J., McKenzie, G.J. & McKenzie, A.N. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585–2591 (2000).
Herbert, D.R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004).
Jankovic, D. et al. Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile. J. Immunol. 163, 337–342 (1999).
Urban, J.F., Jr. et al. IL-13, IL-4Rα, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8, 255–264 (1998).
Wilson, M.S. et al. IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. J. Clin. Invest. 117, 2941–2951 (2007).
McKenzie, G.J., Fallon, P.G., Emson, C.L., Grencis, R.K. & McKenzie, A.N. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J. Exp. Med. 189, 1565–1572 (1999).
Noben-Trauth, N. et al. An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. Proc. Natl. Acad. Sci. USA 94, 10838–10843 (1997).
Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245–248 (1993).
Herrick, C.A., Xu, L., McKenzie, A.N., Tigelaar, R.E. & Bottomly, K. IL-13 is necessary, not simply sufficient, for epicutaneously induced Th2 responses to soluble protein antigen. J. Immunol. 170, 2488–2495 (2003).
Cocks, B.G., de Waal Malefyt, R., Galizzi, J.P., de Vries, J.E. & Aversa, G. IL-13 induces proliferation and differentiation of human B cells activated by the CD40 ligand. Int. Immunol. 5, 657–663 (1993).
Punnonen, J. et al. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc. Natl. Acad. Sci. USA 90, 3730–3734 (1993).
Emson, C.L., Bell, S.E., Jones, A., Wisden, W. & McKenzie, A.N. Interleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13. J. Exp. Med. 188, 399–404 (1998).
Anthony, R.M. et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat. Med. 12, 955–960 (2006).
Wynn, T.A. Fibrotic disease and the TH1/TH2 paradigm. Nat. Rev. Immunol. 4, 583–594 (2004).
Zimmermann, N. et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J. Clin. Invest. 111, 1863–1874 (2003).
Loke, P., MacDonald, A.S., Robb, A., Maizels, R.M. & Allen, J.E. Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact. Eur. J. Immunol. 30, 2669–2678 (2000).
Herbert, D.R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004).
Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001).
Lee, C.G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1. J. Exp. Med. 194, 809–821 (2001).
Yang, M. et al. Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness. J. Immunol. 177, 5595–5603 (2006).
Odegaard, J.I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).
Mentink-Kane, M.M. et al. IL-13 receptor α2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc. Natl. Acad. Sci. USA 101, 586–590 (2004).
Katona, I.M., Urban, J.F., Jr., Scher, I., Kanellopoulos-Langevin, C. & Finkelman, F.D. Induction of an IgE response in mice by Nippostrongylus brasiliensis: characterization of lymphoid cells with intracytoplasmic or surface IgE. J. Immunol. 130, 350–356 (1983).
Pesce, J. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116, 2044–2055 (2006).
Adams, N.C. & Gale, N.W. in Mammalian and Avian Transgenesis–New Approaches (eds. Pease, S. & Lois, C.) 131–172 (Springer, Berlin-Heidelberg, 2006).
Dickensheets, H., Venkataraman, C., Schindler, U. & Donnelly, R. Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Proc. Natl. Acad. Sci. USA 96, 10800–10805 (1999).
Acknowledgements
We thank R. Thompson, S. White and the animal care technicians for technical assistance; F. Lewis and the Biomedical Research Institute for S. mansoni cercariae; and M. Karow (Regeneron) for discussions. Supported by the intramural research program of the National Institutes of Health–National Institute of Allergy and Infectious Diseases, and Regeneron.
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T.R.R. designed and did experiments and contributed to the manuscript; J.T.P., F.S., M.M.M.-K. and M.S.W. designed and did experiments; A.W.C. and J.F.U. assisted in animal experiments, scoring and data analysis; S.S., D.M.V., A.J.M. and G.D.Y. provided the Il13ra1−/− mice and assisted in writing the manuscript; R.P.D. designed and assisted in experiments; and T.A.W. designed and supervised the project, designed and assisted in experiments, and helped write the manuscript.
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S.S., D.M.V., W.J.M and G.D.Y were employees of Regeneron Pharmaceuticals at the time this work was done.
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Ramalingam, T., Pesce, J., Sheikh, F. et al. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor α1 chain. Nat Immunol 9, 25–33 (2008). https://doi.org/10.1038/ni1544
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DOI: https://doi.org/10.1038/ni1544
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