MIF Synergizes with Trypanosoma cruzi Antigens to Promote Efficient Dendritic Cell Maturation and IL-12 Production via p38 MAPK

Abstract

Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of the MIF-dependent responses to Trypanosoma cruzi, we investigated host resistance in MIF-/- mice (on the BALB/c background) during an intraperitoneal infection. We focused on the potential involvement of MIF in dendritic cell (DC) maturation and cytokine production. Following a challenge with 5 x 103 T. cruzi parasites, wild type (WT) mice developed a strong IL-12 response and adequate maturation of the draining mesenteric lymph node DCs and were resistant to infection. In contrast, similarly infected MIF-/- mice mounted a weak IL-12 response, displayed immature DCs in the early phases of infection and rapidly succumbed to T. cruzi infection. The lack of maturation and IL-12 production by the DCs in response to total T. cruzi antigen (TcAg) was confirmed by in vitro studies. These effects were reversed following treatment with recombinant MIF. Interestingly, TcAg-stimulated bone marrow-derived DCs from both WT and MIF-/- mice had increased ERK1/2 MAPK phosphorylation. In contrast, p38 phosphorylation was only upregulated in WT DCs. Reconstitution of MIF to MIF-/- DCs upregulated p38 phosphorylation. The MIF-p38 pathway affected MHC-II and CD86 expression as well as IL-12 production. These findings demonstrate that the MIF-induced early DC maturation and IL-12 production mediates resistance to T. cruzi infection, probably by activating the p38 pathway.

The Role of MIF in Type 1 and Type 2 Diabetes Mellitus

“…Considering that the insulitis process marks the beginning of the disease and is an autoimmune inflammatory process, we propose the hypothesis that MIF plays an important role in insulitis onset or development. This hypothesis is supported by studies in which MIF was found to play important roles in the processes of antigen presentation and inflammatory cell activation [13, 51]. However, additional studies should be performed to establish the mechanism related to the role of MIF in T1DM.…”

Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

“…That p38 MAPK signaling is important for EBOV replication in macrophages and DCs has precedence. EBOV infection induces MAPK signaling cascades in a GP-dependent manner (Martinez et al, 2007; Wahl-Jensen et al, 2011), and p38 MAPK is thought to play dual roles in DC maturation and induction of inflammatory cytokines (Ayala et al, 2000; Lee et al, 2009; Terrazas et al, 2011). …”

“…p38 MAPK signaling has also been implicated as playing a role in the viral transcription and translation of a number of viruses including hepatitis C virus, avian reovirus, porcine circovirus type 2, porcine reproductive and respiratory syndrome virus, rotavirus, Kaposi sarcoma-associated herpesvirus, encephalomyocarditis virus and HIV-1 (Cohen et al, 1997; George et al, 2012; Hirasawa et al, 2003; Jafri et al, 2007; Ji et al, 2009; Lee and Lee, 2012; Pan et al, 2006; Wei et al, 2009); and inhibition of p38 MAPK signaling has been shown to directly inhibit virus infection (Chang et al, 2008; Ludwig et al, 2003; Wei et al, 2009). EBOV infection induces MAPK signaling cascades in a GP-dependent manner, and p38 MAPK is thought to play dual roles in DC maturation and induction of inflammatory cytokines (Ayala et al, 2000; Lee et al, 2009; Terrazas et al, 2011). These facts motivated our analysis of p38 MAPK inhibitors on viral replication and entry.…”

Elevated Serum Levels of Macrophage Migration Inhibitory Factor Are Associated with Progressive Chronic Cardiomyopathy in Patients with Chagas Disease

“…In Chagas disease, early MIF induction in target tissues from infected hosts has been reported as a crucial step for resistance to acute T. cruzi infection [46]–[48]. On the other hand, MIF and TNF-α are important for the lethal synergism between T. cruzi infection and LPS-induced shock [49].…”