Insulin-Like Growth Factor-I as an Effector Element of the Cytokine IL-4 in the Development of a Leishmania major Infection.

Certain cytokines modulate the expression of insulin-like growth factor- (IGF-) I. Since IL-4 and IGF-I promote growth of the protozoan Leishmania major, we here addressed their interaction in downregulating the expression of Igf-I mRNA using small interfering RNA (siRNA) in Leishmania major-infected macrophages. Parasitism was decreased in the siRNA-treated cells compared with the nontreated cells, reversed by the addition of recombinant IGF-I (rIGF-I). In IL-4-stimulated macrophages, parasitism and the Igf-I mRNA amount were increased, and the effects were nullified upon siRNA transfection. IGF-I downregulation inhibited both parasite and macrophage arginase activation even in IL-4-stimulated cells. Searching for intracellular signaling components shared by IL-4 and IGF-I, upon siRNA transfection, phosphorylated p44, p38, and Akt proteins were decreased, affecting the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. In L. major-infected C57BL6-resistant mice, the preincubation of the parasite with rIGF-I changed the infection profile to be similar to that of susceptible mice. We conclude that IGF-I constitutes an effector element of IL-4 involving the PI3K/Akt pathway during L. major infection.

Treatment of African trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model.

There is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We show here that intraperitoneal injection of the adenosine analogue cordycepin (3'-deoxyadenosine), together with an adenosine deaminase (ADA) inhibitor (coformycin or deoxycoformycin), cures Trypanosoma brucei brucei infection in mice. Treatment was also effective at a stage when the trypanosomes had penetrated into the brain parenchyma, as determined by double immunolabeling of parasites and cerebral vessel endothelial cells in brain sections. At this stage, the parasites were eliminated not only from the blood but also from the brain parenchyma. In parallel with the elimination of parasites, in treated mice, the number of CD45+ inflammatory cells in the brain parenchyma was reduced. Treatment was not immunosuppressive. In vitro incubation with cordycepin reduced the growth of T. brucei brucei and T. cruzi, as well as Leishmania major and L. amazonensis. Administration of cordycepin plus deoxycofomycin to T. cruzi-infected mice also significantly reduced parasitemia. Accordingly, we propose nucleoside analogues resistant to ADA as candidates for treatment of late-stage HAT.