Endogenous interleukin-12 is critical for controlling the late but not the early stage of Leishmania mexicana infection in C57BL/6 mice

Abstract

The role of interleukin-12 (IL-12) has been clearly established in the resistance of C57BL/6 (B6) mice to Leishmania major infection, but its involvement in the control of Leishmania mexicana infection remains to be determined. Here, we show the following. (i) L. mexicana, in contrast to L. major, induces the development of nonhealing lesions in B6 mice. (ii) Cells expressing IL-12p40, gamma interferon (IFN-gamma), NOS2, and CD40L are numerous in the footpad lesion and/or the draining popliteal lymph node of animals infected for up to 14 weeks with L. mexicana. (iii) B6 mice, either IL-12p40 deficient or treated with IL-12p40-neutralizing antibodies, display a dramatic enhancement of primary and secondary lesions leading to death 10 weeks after inoculation with L. mexicana. (iv) Splenocytes harvested 4 and 8 weeks after infection of IL-12p40(-/-) B6 mice with L. mexicana are unable to produce IFN-gamma, but secrete IL-4, IL-10, and IL-18. Thus, the early control of L. mexicana infection by B6 mice is independent of IL-12, whereas IL-12 and Th1 responses play a key role in controlling the late stages of L. mexicana infection. However, they fail to resolve lesions, in contrast to L. major infection, emphasizing the different outcomes induced by these two Leishmania species in B6 mice.

FIG. 1.

Size of primary footpad lesions in B6 mice infected with L. mexicana or L. major. Results are expressed as means ± standard errors obtained from 18 animals infected with L. mexicana and 13 animals infected with L. major. ∗∗, P < 0.001 (Student's t test for comparison of L. mexicana and L. major infections).

FIG. 2.

Size of primary footpad lesions in B6 mice receiving anti-IL-12p40 antibodies and infected with L. mexicana. Results are expressed as means ± standard errors (n = 5 in both animal groups). ∗∗, P < 0.001 (Student's t test for comparisons between the two groups).

FIG. 3.

Size of primary footpad lesions in IL-12p40^−/− B6 mice infected with L. mexicana (A) or L. major (C) and parasite burdens in lesions of L. mexicana-infected animals (B). Results are expressed as means ± standard errors. Four IL-12p40^−/− mice and seven WT mice were inoculated with L. mexicana or L. major, and two animals of each group were used for determination of parasite burdens. ∗∗, P < 0.001 (Student's t test for comparison of IL-12p40^−/− and WT mice). †, results from wpi 16 onward are from one mouse.