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Previously, we have shown that macrophage migration inhibitory factor (MIF) was highly elevated in the placental intervillous blood (IVB) of Plasmodium falciparum-infected women. Here, we compared the expression of MIF in placental tissues obtained from P. falciparum-infected and -uninfected women. Immunoperoxidase staining showed a consistent pattern of MIF expression in syncytiotrophoblasts, extravillous trophoblasts, IVB mononuclear cells, and amniotic epithelial cells, irrespective of their malaria infection status. Cytotrophoblast, villous stroma, and Hofbauer cells showed focal staining. Only amniotic epithelial and IVB mononuclear cells from P. falciparum-infected placentas exhibited significantly higher level of MIF expression than uninfected placentas. Stimulation of syncytilized human trophoblast BeWo cells with P. falciparum-infected erythrocytes that were selected to bind these cells resulted in significant increases in MIF secretion, whereas control erythrocytes, lipopolysaccharides, and synthetic beta-hematin had minimal effect. These findings suggest that placental malaria modulates MIF expression in different placental compartments.

Pregnant women are at an increased risk for malarial infection. Plasmodium falciparum accumulates in the placenta and is associated with dysregulated immune function and poor birth outcomes. Malarial pigment (hemozoin) also accumulates in the placenta and may modulate local immune function. In this study, the impact of hemozoin on cytokine production by intervillous blood mononuclear cells from malaria-infected placentas was investigated. There was a dose-dependent, suppressive effect of hemozoin on production of gamma interferon (IFN-gamma), with less of an effect on tumor necrosis factor alpha (TNF-alpha) and interleukin-10, in human immunodeficiency virus-seronegative (HIV(-)) women. In contrast, IFN-gamma and TNF-alpha production tended to increase in HIV-seropositive women with increasing hemozoin levels. Production patterns of cytokines, especially IFN-gamma in HIV(-) women, followed different trends as a function of parasite density and hemozoin level. The findings suggest that the influences of hemozoin accumulation and high-density parasitemia on placental cytokine production are not equivalent and may involve different mechanisms, all of which may operate differently in the context of HIV infection. Cytokine production dysregulated by accumulation of hemozoin or high-density parasitemia may induce pathology and impair protective immunity in HIV-infected and -uninfected women.

Interleukin-12 (IL-12) has been inversely associated with disease severity in human and murine malaria, and a polymorphism in the IL-12 p40 subunit gene (IL12B) has been associated with susceptibility to human cerebral malaria and reduced nitric oxide (NO) production. To better define the relationships between IL-12, NO, malaria parasitemia, and IL12B polymorphisms during malarial tolerance, plasma IL-12 levels and peripheral blood mononuclear cell NO synthase (NOS) activity were measured in asymptomatic Papua New Guineans exposed to intense malaria transmission. The IL-12 level was strongly inversely correlated with the density of Plasmodium falciparum parasitemia (rho = -0.45; P < 0.001) and was predicted to decrease by 19% (95% confidence interval [CI], 10 to 27%) for each twofold increase in P. falciparum parasitemia. This is consistent with a suppressive effect of parasitemia on IL-12 production, an effect previously shown in vitro and in rodent models of disease. The IL-12 level was inversely correlated with NOS activity (r = -0.22; P = 0.007), with each twofold increase in NOS activity being predictive of a 25% (95% CI, 7 to 38%) decrease in plasma IL-12 levels. This probably reflects additional down-regulation of IL-12 by the high basal NO production and monocyte NOS expression found in the malaria-tolerant state. Neither the IL-12 level nor NOS activity was associated with either of two IL12B polymorphisms, reflecting the diversity of genetic control over immune responses in different populations.