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Abstract
Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine, which mediates the regulation of diverse cellular functions. It is produced by extravillous trophoblastic cells and has been found to be involved in the pathogenesis of diseases caused by some protozoa, including Toxoplasma gondii. Previous studies demonstrated the ability of T. gondii to take advantage of MIF action in human trophoblast cells. However, MIF action in T. gondii-infected extravillous trophoblastic cells (HTR8/SVneo cell line) has not been fully investigated. The present study aimed to investigate the role of MIF in T. gondii-infected HTR8/SVneo cells and verify the intracellular signaling pathways triggered by this cytokine. We found that T. gondii increased MIF production by HTR8/SVneo cells, and by contrast, MIF inhibition, by ISO-1, led to a significant decrease in T. gondii proliferation and CD74 expression in HTR8/SVneo cells. Moreover, in infected HTR8/SVneo cells, the addition of recombinant MIF (rMIF) increased CD44 co-receptor expression, ERK1/2 phosphorylation, COX-2 expression, and IL-8 production, which favored T. gondii proliferation. Our findings indicate that T. gondii can use MIF to modulate important factors in HTR8/SVneo cells, being a possible explanation for the higher susceptibility of extravillous trophoblast cells than other trophoblast cell populations.
Highlights
Toxoplasma gondii, the agent of toxoplasmosis, is an obligate intracellular protozoan parasite and a member of the phylum Apicomplexa (Schluter et al, (2014)
When the cells were treated with ISO-1, regardless of T. gondii infection, a decrease in migration inhibitory factor (MIF) production was detected when compared to T. gondii-infected (Tg) cells (p < 0.05, Figure 2A)
In order to understand the increase in T. gondii proliferation when HTR8/SVneo cells were treated with recombinant MIF (rMIF), we investigated the expression of the MIF receptor/co-receptor, CD74/CD44, since it has been shown that T. gondii can modulate and regulate the induction of CD74 expression in infected antigen presenting cells (Louis-Philippe et al, 2015) and the expression of CD44 in macrophages (Seipel et al, 2010; Hayashi et al, 2014)
Summary
Toxoplasma gondii, the agent of toxoplasmosis, is an obligate intracellular protozoan parasite and a member of the phylum Apicomplexa (Schluter et al, (2014). The classical immune response to T. gondii is based on a pro-inflammatory profile, with the production of pro-inflammatory cytokines, such as interleukin (IL)-12, which is produced by macrophages and dendritic cells (DCs) in response to Toll-like receptors (TLRs; Yarovinsky, 2014), in addition to interferon gamma (IFN-γ) released by T cells (Murakami et al, 2002). Another cytokine with a key role in T. gondii infection is macrophage migration inhibitory factor (MIF), produced by different cell types and tissues (Bernhagen et al, 1998). MIF has been shown to participate in both innate and adaptive immune responses (Bloom and Bennett, 1966; David, 1966; Calandra et al, 1995; Calandra and Roger, 2003; Larson and Horak, 2006; Kudrin and Ray, 2008)
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