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Infection and Immunity, November 2004, p. 6287-6293, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6287-6293.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interleukin-10 (IL-10) Counterregulates IL-4-Dependent Effector Mechanisms in Murine Filariasis

Institute for Medical Parasitology, Friedrich Wilhelm University of Bonn, Bonn,¹ Department of Helminthology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany,² Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland³

Received 18 February 2004/ Returned for modification 26 March 2004/ Accepted 25 July 2004

Interleukin-10 (IL-10) was at first described as a Th2-associated cytokine, although more recent reports have shown that immunosuppression applies to both Th1 and Th2 cell responses, e.g., when produced by T regulatory cells. This concept when applied to human filariasis would argue that high parasite loads are associated with IL-10, while bona fide Th2 responses, mediated by IL-4, IL-5, and IL-13, are associated with parasite containment. To prove this relationship in a causal manner, we investigated the roles of IL-4 and IL-10 in a helminth infection model in which mice genetically deficient for IL-4, IL-10, or IL-4 plus IL-10 were infected with the rodent filaria Litomosoides sigmodontis. Compared to C57BL/6 wild-type and IL-10 knockout (KO) mice, IL-4 KO mice remained susceptible, exhibiting a remarkable number of live adult worms. Interestingly however, when the IL-10 gene was knocked out simultaneously with the IL-4 gene, the susceptibility of IL-4 KO mice was reversed. Although production of IFN- was increased in IL-4/IL-10 double-knockout mice, depletion of gamma interferon did not affect worm elimination, so it seems unlikely to be the major factor in mediating resistance in IL-4/IL-10 KO mice. Taken together, the results of this study add proof to the concept that has arisen for human filariasis that IL-10-dependent responses, which are associated with patency, are antagonistic to bona fide Th2 responses, which control parasite loads. The finding that knockout of IL-10 reversed a disease phenotype induced by knockout of IL-4 gives the first causal evidence of an antagonistic activity between IL-4 and IL-10 in an infection in vivo.

Editor: J. F. Urban, Jr.

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