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Infection and Immunity, July 2003, p. 3787-3793, Vol. 71, No. 7
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.7.3787-3793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination of Histoplasma capsulatum

Lucy A. Gildea,1,2,{dagger} Reta Gibbons,2,3 Fred D. Finkelman,1,2 and George S. Deepe Jr.2,3*

Cincinnati Veterans Affairs Medical Center and the Divisions of Immunology,1 Infectious Diseases, Cincinnati, Ohio 45220,3 University of Cincinnati College of Medicine, Cincinnati, Ohio 452672

Received 7 March 2003/ Returned for modification 1 April 2003/ Accepted 14 April 2003

Protection against the pathogenic fungus Histoplasma capsulatum requires Th1 cytokines. Since interleukin-4 (IL-4) can inhibit both Th1 cytokine production and activity, we examined the effects of overproduction of IL-4 in the lung on the course of pulmonary histoplasmosis. IL-4 lung transgenic mice manifested a higher fungal burden in their lungs, but not spleens, compared to wild-type infected controls. Despite the higher burden, the transgenic animals were ultimately capable of controlling infection. The adverse effects of IL-4 on H. capsulatum elimination were not observed during the early phase of infection (days 1 to 3) but were maximal at day 7 postinfection, prior to the induction of cell-mediated immunity. Analysis of total body and lung cytokine levels revealed that gamma interferon and tumor necrosis factor alpha production were not inhibited in the presence of excess IL-4. Our results with transgenic mice were supported by additional in vivo studies in which allergen induction of pulmonary IL-4 was associated with delayed clearance of H. capsulatum yeast and increased fungal burden. These findings demonstrate that excess production of endogenous IL-4 modulates protective immunity to H. capsulatum by delaying clearance of the organism but does not prevent the generation of a Th1 response that ultimately controls infection.

* Corresponding author. Mailing address: Division of Infectious Diseases, 231 Albert Sabin Way, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0560. Phone: (513) 558-4704. Fax: (513) 558-2089. E-mail: george.deepe{at}uc.edu.

Editor: T. R. Kozel

{dagger} Present address: Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45253-8707.

Infection and Immunity, July 2003, p. 3787-3793, Vol. 71, No. 7
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.7.3787-3793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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