Migration-inhibitory factor gene-deficient mice are susceptible to cutaneous Leishmania major infection

To determine the role of endogenous migration-inhibitory factor (MIF) in th e development of protective immunity against cutaneous leishmaniasis, we an alyzed the course of cutaneous Leishmania major infection in MIF gene defic ient mice (MIF-/-) and wild-type (MIF+/+) mice. Following cutaneous L. majo r infection, MIF-/- mice were susceptible to disease and developed signific antly larger lesions and greater parasite burdens than MIF+/+ mice, Interes tingly, antigen-stimulated lymph node cells from MIF-/- mice produced more interleukin-4 (IL-4) and gamma interferon (IFN-gamma) than those from MIF+/ + mice, although the differences were statistically not significant. IFN-ga mma -activated resting peritoneal macrophages front MIF-/- mice showed impa ired macrophage leishmanicidal activity and produced significantly lower le vels of nitric oxide and superoxide in vitro. The macrophages from MIF-/- m ice, however, produced much more IL-6 than macrophages from wild-type mice. These findings demonstrate that endogenous MIF plays an important role in the development of protective immunity against L. major in vivo. Furthermor e, they indicate that the susceptibility of MIF-/- mice to L, major infecti on is due to impaired macrophage leishmanicidal activity rather than dysreg ulation of Th1 and Th2 responses.