The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

Abstract

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 α-chain (IL-4Rα), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4Rα−/− mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4Rα−/− mice were crossed with BALB/c IL-10−/− mice. In contrast to the lack of resistance conferred by IL-4Rα 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-4Rα−/− mice and IL-4Rα × IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4Rα−/− mice infected with L. major IR173. Production of IFN-γ was only increased relative to wild-type or littermate controls in IL-4Rα−/− mice with complementary defects in IL-10. Comparisons of IFN-γ-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-γ 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-γ mediated killing.

Measurement of Serum Levels of Interleukin 17 and 23 in the Immune System with Different Amounts of Spleens White Pulp Size after Inoculation of New Leishmania Vaccine in Susceptible Mice

“…Our results from post vaccination and pre challenging are desirable and as it was demonstrated in the present experiment, the best vaccinated group was LT group and the best injection dose was 100 µg/0.1 ml nominated LT100 which had lowest spleen white pulp expansion and highest levels of IL-17 and IL-23. These finding confirmed our previous results concerning expansion of spleen white pulp [35] and the levels of serum IL17 and IL-23 in the vaccinated animals [36][37][38][39][40]41]. This is a satisfactory results for this new leishmania Vaccine, since IL-23 and IL-17 axis and activation of JAK-STAT is essential for immunity against Chronic Mucocutaneous Candidiasis (CMCC) and CMCC also is Mendelian disease that leishmaniasis is one of its Complications.…”

The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis

“…A recent study reported similar observations with L. major infection and implicated both IL-4R signaling and IL-10 to contribute to susceptibility, and found that BALB/c mice deficient in both IL-4R␣ and IL-10 are more resistant to L. major infection, regardless of parasite substrain. However, in relative terms, IL-10 appears to exert a more profound effect on L. major parasite growth and the development of disease (33).…”

The MyD88 protein 88 pathway is differently involved in immune responses induced by distinct substrains of Leishmania major

“…Neutralization of endogenous IL-4 results in a robust Th1 response in susceptible BALB/c mice [10,14,15]. MyD88 À/À C57BL/6 mice treated with anti-IL-4 mAb prior to infection with L. major IR75 rendered these mice resistant, whereas neutralization of IL-4 in MyD88 À/À C57BL/6 mice infected with L. major LV39 did not have the same effect.…”

“…Macrophages infected with IR173 and Friedlin V1 substrains required 25-500 fold lower concentration of IFN-g to achieve the same level of parasite killing as LV39 [10]. Similarly, IR75 substrain required tenfold lower concentration of IFN-g to achieve the same level of parasite killing than LV39 (Revaz-Breton, unpublished data).…”

“…IL-4 and IFN-g production was also analyzed in MyD88 [8,9]. Several observations indicated that IL-13 is involved in the susceptibility to infection with L. major LV39 [10]. As shown in Fig.…”