Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2−/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice.

[1]  D. Cockayne,et al.  IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-alpha, IFN-gamma, and IL-12 production. , 1997, Journal of immunology.

[2]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[3]  T. Mosmann,et al.  Continuous administration of Il-13 to mice induces extramedullary hemopoiesis and monocytosis. , 1996, Journal of immunology.

[4]  T. Wynn,et al.  An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. , 1999, The Journal of clinical investigation.

[5]  R. Fernandez-Botran,et al.  Evidence that natural murine soluble interleukin 4 receptors may act as transport proteins , 1991, The Journal of experimental medicine.

[6]  T. Wynn,et al.  IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs. , 1999, Journal of immunology.

[7]  F. Nicoletti,et al.  Prevention of endotoxin‐induced lethality in neonatal mice by interleukin‐13 , 1997, European journal of immunology.

[8]  Bryan R. G. Williams,et al.  Protein-tyrosine Phosphatase Shp-1 Is a Negative Regulator of IL-4- and IL-13-dependent Signal Transduction* , 1998, Journal of Biological Chemistry.

[9]  R. Coffman,et al.  Modulation of murine macrophage function by IL-13. , 1993, Journal of immunology.

[10]  D D Donaldson,et al.  The role of IL-13 in helminth-induced inflammation and protective immunity against nematode infections. , 1999, Current opinion in immunology.

[11]  R. Strieter,et al.  Expression and Contribution of Endogenous IL-13 in an Experimental Model of Sepsis1 , 2000, The Journal of Immunology.

[12]  C. Bogdan,et al.  Mechanism of suppression of macrophage nitric oxide release by IL-13: influence of the macrophage population. , 1997, Journal of immunology.

[13]  A. Sher,et al.  IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. , 1992, Journal of immunology.

[14]  D D Donaldson,et al.  The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. , 1998, Journal of immunology.

[15]  R. Puri,et al.  Interleukin-13 receptor alpha' but not alpha chain: a functional component of interleukin-4 receptors. , 1998, Blood.

[16]  J. Lélias,et al.  Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain. , 1996, The Journal of biological chemistry.

[17]  S. McKnight,et al.  Components of a Stat recognition code: evidence for two layers of molecular selectivity. , 1995, Immunity.

[18]  G. Zurawski,et al.  Receptors for interleukin‐13 and interleukin‐4 are complex and share a novel component that functions in signal transduction. , 1993, The EMBO journal.

[19]  S. Akira,et al.  Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. , 1996, Journal of immunology.

[20]  M. Wills-Karp Immunologic basis of antigen-induced airway hyperresponsiveness. , 1999, Annual review of immunology.

[21]  R. Puri,et al.  cDNA Cloning and Characterization of the Human Interleukin 13 Receptor α Chain* , 1996, The Journal of Biological Chemistry.

[22]  W. Wisden,et al.  Interleukin (IL)-4–independent Induction of Immunoglobulin (Ig)E, and Perturbation of  T Cell Development in Transgenic Mice Expressing IL-13 , 1998, The Journal of experimental medicine.

[23]  T. Mosmann,et al.  Mouse IL-13 enhances antibody production in vivo and acts directly on B cells in vitro to increase survival and hence antibody production. , 1999, Journal of immunology.

[24]  R. Puri,et al.  Interleukin-13 Receptor α′ But Not α Chain: A Functional Component of Interleukin-4 Receptors , 1998 .

[25]  F. Finkelman,et al.  Stat6 Regulation of In Vivo IL-4 Responses1 , 2000, The Journal of Immunology.

[26]  R. de Waal Malefyt,et al.  Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D B Corry,et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. , 1998, Science.

[28]  G. McKenzie,et al.  Impaired development of Th2 cells in IL-13-deficient mice. , 1998, Immunity.

[29]  A. Mantovani,et al.  IL-13 inhibits TNF production but potentiates that of IL-6 in vivo and ex vivo in mice. , 1997, Journal of immunology.

[30]  A. Mantovani,et al.  Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells , 1995, The Journal of experimental medicine.

[31]  R. Puri,et al.  The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. , 2001, Blood.

[32]  F. Finkelman,et al.  IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. , 1998, Immunity.

[33]  T. Wynn,et al.  Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response , 2003, The Journal of experimental medicine.

[34]  J. Langhorne,et al.  The immune response to Plasmodium chabaudi malaria in interleukin‐4‐deficient mice , 1994, European journal of immunology.

[35]  S. Gordon,et al.  Interleukin‐13 alters the activation state of murine macrophages in vitro: Comparison with interleukin‐4 and interferon‐γ , 1994, European journal of immunology.

[36]  J. Lélias,et al.  Cloning and Characterization of a Specific Interleukin (IL)-13 Binding Protein Structurally Related to the IL-5 Receptor α Chain* , 1996, The Journal of Biological Chemistry.

[37]  F. Finkelman,et al.  Recombinant soluble murine IL-4 receptor can inhibit or enhance IgE responses in vivo. , 1993, Journal of immunology.

[38]  K. Bost,et al.  In vivo treatment with anti‐interleukin‐13 antibodies significantly reduces the humoral immune response against an oral immunogen in mice , 1996, Immunology.

[39]  J. G. Zhang,et al.  Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Moritz,et al.  Identification, Purification, and Characterization of a Soluble Interleukin (IL)-13-binding Protein , 1997, The Journal of Biological Chemistry.