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

Abstract

Recent studies have demonstrated the critical role of IL-10 in susceptibility to cutaneous and visceral leishmaniasis caused by Leishmania major and Leishmania donovani, respectively. To determine whether IL-10 also plays a similar role in the susceptibility and pathogenesis of cutaneous leishmaniasis caused by the New World species, L. mexicana and L. amazonensis, we analyzed their course of infection in IL-10-deficient BALB/c mice and their wild-type counterparts. Although IL-10-deficient mice infected with either L. mexicana or L. amazonensis failed to control the lesion progression, we did observe consistently lower levels of infection in IL-10−/− mice compared with wild-type BALB/c mice. We also observed increased IFN-γ and NO production and higher levels for IL-12p40 and IL-12Rβ2 mRNA in cells from IL-10−/− mice compared with cells from BALB/c mice. The mRNA levels for IL-4, which increased significantly in both IL-10−/− and BALB/c mice, were comparable. When treated with anti-IL-4 mAb, IL-10−/− mice resolved the infection more effectively and had significantly fewer parasites in their lesions compared with similarly treated BALB/c mice. These findings suggest that IL-10, although not the dominant mediator of susceptibility of BALB/c mice to infection with L. mexicana and L. amazonensis, does play a significant role in regulating the development of a protective Th1-type response. However, effective resolution of infection with these New World parasites requires neutralization of both IL-4 and IL-10.

Control of Infection withLeishmania majorin Susceptible BALB/c Mice Lacking the Common γ-Chain for FcR Is Associated with Reduced Production of IL-10 and TGF-β by Parasitized Cells

“…BALB/c mice deficient in IL-10 control L. major infection and harbor reduced parasite numbers (13), and IL-10-deficient C57BL/6 mice or C57BL/6 mice treated with anti-IL-10R Ab achieve sterile cure of L. major infection (28). In addition, we have shown that IL-10-deficient mice exhibit a dramatic increase in resistance to infection with Leishmania donovani and L. mexicana complex parasites (29,30). As is the case with IL-10, a number of studies have shown that neutralization of TGF-␤ promotes enhanced resistance to both cutaneous and visceral leishmaniasis (31,32).…”

Despite Increased CD4+Foxp3+ Cells within the Infection Site, BALB/c IL-4 Receptor-Deficient Mice Reveal CD4+Foxp3-Negative T Cells as a Source of IL-10 inLeishmania majorSusceptibility

“…In mouse models of leishmaniasis, IL-10 secretion has been shown to be detrimental to infection with cutaneous strains such as L. major, Leishmania mexicana, and Leishmania amazonensis (6,7,(35)(36)(37), and to the visceral strain Leishmania donovani (38 -40). The dependence on IL-10 in determining disease outcome may also depend on the particular substrain of L. major, as has been documented with L. major LV39 (6) and L. major Seidman (35).…”

PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

“…Both FccR and circulating IgG are needed for chronic disease, suggesting that ligation of FccR on macrophages by Leishmania-specific IgG triggers IL-10 production. IL-10 can act to inhibit nitric oxide synthesis, IL-12 and antigen presentation, and suppresses protective immunity [21,22].…”