Interleukin-10 (IL-10) counterregulates IL-4-dependent effector mechanisms in Murine Filariasis.
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-gamma 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.
Specht
Sabine
S
Institute for Medical Parasitology, Friedrich Wilhelm University of Bonn, Sigmund-Freud-Str. 25, 53105, Germany.
Volkmann
Lars
L
Wynn
Tom
T
Hoerauf
Achim
A
D000818:Animals; D005368:Filariasis / Q000276:immunology* / Q000469:parasitology; D005370:Filarioidea / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D016753:Interleukin-10; D015847:Interleukin-4