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The Journal of Immunology, 2003, 170: 5152-5158.
Copyright © 2003 by The American Association of Immunologists

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility to Leishmania major1

Nancy Noben-Trauth2,*, Rosalia Lira3,{dagger}, Hisashi Nagase*, William E. Paul{ddagger} and David L. Sacks{dagger}

* Department of Immunology, George Washington University Medical Center, Washington, DC 20037; and {dagger} Laboratory of Parasitic Diseases and {ddagger} Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R {alpha}-chain (IL-4R{alpha}), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4R{alpha}-/- mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4R{alpha}-/- mice were crossed with BALB/c IL-10-/- mice. In contrast to the lack of resistance conferred by IL-4R{alpha} gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4R{alpha}-/- mice and IL-4R{alpha} x IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4R{alpha}-/- mice infected with L. major IR173. Production of IFN-{gamma} was only increased relative to wild-type or littermate controls in IL-4R{alpha}-/- mice with complementary defects in IL-10. Comparisons of IFN-{gamma}-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-{gamma} than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-{gamma} mediated killing.


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