Induction of IL-12 production in human peripheral monocytes by Trypanosoma cruzi Is mediated by glycosylphosphatidylinositol-anchored mucin-like glycoproteins and potentiated by IFN- γ and CD40-CD40L interactions.

Lúcia Cristina Jamli Abel,Isabela Cunha Navarro,Ricardo Tostes Gazzinelli,Edecio Cunha-Neto,Ludmila Rodrigues Pinto Ferreira,Jorge Kalil,Monique Andrade Baron,Luiz Vicente Rizzo

doi:10.1155/2014/345659

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-γ secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products—like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)—are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γ primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-γ. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.

Highlights

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, which affects approximately 15 million people in South and Central America [1, 2]
Similar results were obtained when tGPI mucin was used as stimulus (Figure 4(b)) suggesting that these molecules may be the effectors in the T. cruziinduced IL-12 production in humans, as has been previously described in mice [8]. We observed that both living trypomastigotes and tGPI-mucins are potent inducers of IL-12 production in human monocytes and that this effect depends on CD40CD40L interaction and IFN-γ signaling
When parasites were deliberately added to cocultures of irradiated peripheral blood mononuclear cells (PBMC) and activated T cell lines, we observed again high levels of IL12 expression in PBMC, the T. cruzi stimulus itself was capable of inducing some IL-12 expression by PBMC in the absence of activated T cells

Summary

Introduction

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, which affects approximately 15 million people in South and Central America [1, 2]. Mediators of Inflammation cytokines by ligands of innate immunity receptors of T. cruzi is considered important in the control of infection and outcome of Chagas disease [5, 6]. It has been extensively described that glycosylphosphatidylinositol-anchored mucins-like glycoproteins from Trypanosoma cruzi trypomastigotes (tGPI-mucins) activate murine macrophages in vitro to produce the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin- (IL-) 12 as well as nitric oxide (NO) [7, 8]. T. cruzi tGPI-mucins were shown to initiate the inflammatory response through an activation of Toll-like receptors TLR2 [7, 13] Different components from this parasite are capable of activating TLRs in dendritic cells and macrophages, like the unmethylated CpG motifs present in T. cruzi genome, were identified as a TLR9 agonist [14]. We assessed the role of IFN-γ and CD40L signaling on T. cruzi and tGPI mucin-induced IL-12 production

Methods

Results

Conclusion