HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, U. Articles by Alber, G. Search for Related Content PubMed PubMed Citation Articles by Müller, U. Articles by Alber, G.

IL-13 Induces Disease-Promoting Type 2 Cytokines, Alternatively Activated Macrophages and Allergic Inflammation during Pulmonary Infection of Mice with Cryptococcus neoformans¹

Uwe Müller^*, Werner Stenzel, Gabriele Köhler, Christoph Werner, Tobias Polte^2,, Gesine Hansen^3,, Nicole Schütze^*, Reinhard K. Straubinger^*, Manfred Blessing^*, Andrew N. J. McKenzie^¶, Frank Brombacher^|| and Gottfried Alber^4,*

^* Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany; Institute of Neuropathology, Medical Faculty, University of Cologne, Cologne, Germany; Gerhard Domagk Institute for Pathology, University of Münster, Münster, Germany; Division of Allergy and Pulmonology, Department of Pediatrics, Martin-Luther-University, Halle-Wittenberg, Halle, Germany; ^¶ Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom; and ^|| Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C. neoformans, IL-13-overexpressing transgenic (IL-13Tg⁺), IL-13-deficient (IL-13^–/–), and wild-type (WT) mice were infected intranasally. Susceptibility to C. neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg⁺ mice. Infected IL-13Tg⁺ mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13^–/– mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg⁺ mice was associated with a significant type 2 cytokine shift but only minor changes in IFN- production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg⁺ mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg⁺ mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-1, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research Grant AL 371/5-2 from the Deutsche Forschungsgemeinschaft (to G.A.) and by Grant AL 371/5-3 from the Federal Ministry for Economic Cooperation and Development (to G.A.) for a research project (with F.B.). F.B. is the holder of a Wellcome Trust Senior Research Fellowship for Medical Science in South Africa from Grant 056708/Z/99 and receives support from the National Research Foundation and Medical Research Council of South Africa.

² Current address: Helmholtz Centre for Environmental Research, Leipzig, Germany.

³ Current address: Department of Pediatrics, Division of Pneumology and Neonatology, Hannover Medical School, Hannover, Germany.

⁴ Address correspondence and reprint requests to Dr. Gottfried Alber, Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tierkliniken 11, 04103 Leipzig, Germany. E-mail address: alber{at}rz.uni-leipzig.de

⁵ Abbreviations used in this paper: WT, wild type; p.i., postinfection; aaMph, alternatively activated macrophage; caMph, classically activated macrophage; iNOS, inducible NO synthase; Tg, transgenic.

This article has been cited by other articles:

				C. H. Y. Fong, M. Bebien, A. Didierlaurent, R. Nebauer, T. Hussell, D. Broide, M. Karin, and T. Lawrence An antiinflammatory role for IKK{beta} through the inhibition of "classical" macrophage activation J. Exp. Med., June 9, 2008; 205(6): 1269 - 1276. [Abstract] [Full Text] [PDF]

				J. M. Dan, R. M. Kelly, C. K. Lee, and S. M. Levitz Role of the Mannose Receptor in a Murine Model of Cryptococcus neoformans Infection Infect. Immun., June 1, 2008; 76(6): 2362 - 2367. [Abstract] [Full Text] [PDF]