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

Luiza C Reis,Frode Selheim,Eduardo Milton Ramos-Sanchez,Hiro Goto,Maria Hernandez-Valladares,Lucile Maria Floeter-Winter,Audun H Nerland,Fabricio Petitto-Assis

doi:10.1155/2018/9787128

Abstract

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.

Highlights

Certain physiological processes are reciprocally controlled by the immune and endocrine systems, where the actions of cytokines and hormones efficiently regulate these processes [1,2,3]
We evaluated the effect on lesion development upon the injection of L. major promastigotes preincubated with recombinant insulin-like growth factor- (IGF-)I into the footpads of BALB/c and C57BL/6 mice, which differ in basal Igf-I mRNA amount
In the cultures stimulated with recombinant IGF-I (rIGF-I), we observed a larger number of parasites that reached the stationary phase earlier than nonstimulated cultures (Figure 1(a))

Summary

Introduction

Certain physiological processes are reciprocally controlled by the immune and endocrine systems, where the actions of cytokines and hormones efficiently regulate these processes [1,2,3] In this context, the observation that certain cytokines modulate the expression of the hormone insulin-like growth factor(IGF-) I [4,5,6] led us to explore this cross talk in the interaction of the Leishmania parasite with host cells since the essential roles of different cytokines and the effect of IGF-I on the development of Leishmania infection are known [7]. Leishmania is an obligatory intracellular protozoan that is transmitted vectorially and causes diseases called leishmaniases that affect two million people globally each year These infections result in lesions on the skin, mucosa, or viscera, depending on the parasite species and the host response and features [8]. Cytokines and growth factors, including IGF-I, act on macrophage leishmanicidal or parasite growth-promoting

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