MIF(Macrophage Migration Inhibitory Factor) Promoter Polymorphisms and Susceptibility to Severe Malarial Anemia

ABSTRACT Severe malarial anemia (SMA), caused by Plasmodium falciparum infections, is one of the leading causes of childhood mortality in sub-Saharan Africa. Although the molecular determinants of SMA are largely undefined, dysregulation in host-derived inflammatory mediators influences disease severity. Macrophage migration inhibitory factor (MIF) is an important regulator of innate inflammatory responses that has recently been shown to suppress erythropoiesis and promote pathogenesis of SMA in murine models. To examine the role of MIF in the development of childhood SMA, peripheral blood MIF production was examined in Kenyan children (aged <3 years, n = 357) with P. falciparum malarial anemia. All children in the study were free from bacteremia and human immunodeficiency virus type 1. Since deposition of malarial pigment (hemozoin [Hz]) contributes to suppression of erythropoiesis, the relationship between MIF concentrations and monocytic acquisition of Hz was also examined in vivo and in vitro. Circulating MIF concentrations declined with increasing severity of anemia and significantly correlated with peripheral blood leukocyte MIF transcripts. However, MIF concentrations in peripheral blood were not significantly associated with reticulocyte production. Multivariate regression analyses, controlling for age, gender, and parasitemia, further revealed that elevated levels of pigment-containing monocytes (PCM) was associated with SMA and decreased MIF production. In addition, PCM levels were a better predictor of hemoglobin and MIF concentrations than parasite density. Additional experiments in malaria-naive individuals demonstrated that hemozoin caused both increased and decreased MIF production in cultured peripheral blood mononuclear cells (PBMC) in a donor-specific manner, independent of apoptosis. However, PBMC MIF production in children with acute malaria progressively declined with increasing anemia severity. Results presented here demonstrate that acquisition of hemozoin by monocytes is associated with suppression of peripheral blood MIF production and enhanced severity of anemia in childhood malaria.

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Macrophage migration inhibitory factor promoter polymorphisms (−794CATT5-7) as potential biomarker for early-stage cervical cancer

Journal of Obstetrics and Gynaecology Research ◽

10.1111/jog.13233 ◽

2017 ◽

Vol 43 (3) ◽

pp. 571-579 ◽

Cited By ~ 2

Author(s):

Suhui Wu ◽

Jingfen Sun ◽

Junfang Lian ◽

Haixia Shang ◽

Huijuan Tao ◽

...

Keyword(s):

Cervical Cancer ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Early Stage ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms ◽

Potential Biomarker ◽

Early Stage Cervical Cancer

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The Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms (rs3063368, rs755622) Predict Acute Kidney Injury and Death after Cardiac Surgery

Journal of Clinical Medicine ◽

10.3390/jcm9092936 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2936

Author(s):

Luisa Averdunk ◽

Jürgen Bernhagen ◽

Karl Fehnle ◽

Harald Surowy ◽

Hermann-Josef Lüdecke ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Elevated Serum ◽

Kidney Injury ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms ◽

Risk Of Death

Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT5–7 (rs5844572/rs3063368,“-794”) and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT7) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40–2.88), p = 0.0001). Carriers of CATT7 were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99–33.14), p = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20–2.43), p = 0.003). Multivariate analyses identified CATT7 predictive for AKI (OR 2.13 (1.46–3.09), p < 0.001) and death (OR 5.58 (1.29–24.04), p = 0.021). CATT7 was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT7 allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.

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Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms Are Associated With Favorable Hemodynamic Indices In Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1881 ◽

2012 ◽

Author(s):

Todd M. Kolb ◽

Danielle Boyce ◽

Nicholas Rafaels ◽

Li Gao ◽

Reda Girgis ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms ◽

Pulmonary Arterial

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Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation

Journal of Endocrinology ◽

10.1677/joe.0.1790015 ◽

2003 ◽

Vol 179 (1) ◽

pp. 15-23 ◽

Cited By ~ 53

Author(s):

JA Baugh ◽

SC Donnelly

Keyword(s):

Inflammatory Response ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Molecular Mechanisms ◽

Adaptive Immune Response ◽

Gene Promoter ◽

Chronic Inflammatory Disease ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms

The diverse actions of macrophage migration inhibitory factor (MIF) within the immuno-neuroendocrine system are yet to be fully understood, but it is clear that MIF plays a pivotal role in the regulation of both the innate and adaptive immune response. An emerging body of data presently indicates that MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control the 'set point' and magnitude of the immune and inflammatory response. In this article we will review the actions of MIF within the immune system and discuss the overlapping and contrasting aspects of MIF and glucocorticoid biology. In particular we will focus on the role of MIF within the immuno-neuroendocrine interface and suggest molecular mechanisms by which MIF may counter-regulate glucocorticoid function. Finally we will discuss emerging evidence that functional MIF gene-promoter polymorphisms render one susceptible to elevated MIF expression, and the development of an exaggerated immune/inflammatory response that potentiates the progression to chronic inflammatory disease.

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Macrophage Migration Inhibitory Factor Release by Macrophages after Ingestion of Plasmodium chabaudi-Infected Erythrocytes: Possible Role in the Pathogenesis of Malarial Anemia

Infection and Immunity ◽

10.1128/iai.68.4.2259-2267.2000 ◽

2000 ◽

Vol 68 (4) ◽

pp. 2259-2267 ◽

Cited By ~ 83

Author(s):

James A. Martiney ◽

Barbara Sherry ◽

Christine N. Metz ◽

Marisol Espinoza ◽

Angel S. Ferrer ◽

...

Keyword(s):

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Interleukin 12 ◽

Macrophage Migration ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Erythropoiesis Inhibitor ◽

Necrosis Factor ◽

Malarial Anemia

ABSTRACT Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1β, tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudiinfection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages. MIF, a proinflammatory mediator and counter-regulator of glucocorticoid action, inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three- to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia.

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