scholarly journals Interaction of macrophage-migration-inhibitory factor with haematin

1998 ◽  
Vol 331 (3) ◽  
pp. 905-908 ◽  
Author(s):  
Joanne L. PENNOCK ◽  
Jiraprapa WIPASA ◽  
Michael P. GORDGE ◽  
David J. MEYER
Keyword(s):  
Ionic Strength ◽  
Methyl Ester ◽  
Immune Responses ◽  
Migration Inhibitory Factor ◽  
Human Liver ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
High Yield ◽  
Macrophage Migration ◽  
Low Ionic Strength

Macrophage-migration-inhibitory factor (MIF) is retained by S-hexylglutathione–agarose but is not specifically eluted in high yield. Human liver MIF was purified in high yield using retention by phenyl-agarose at low ionic strength and cation-exchange FPLC as described for bovine lens MIF [Rosengren, Bucala, Åman, Jacobsson, Odh, Metz and Rorsman (1996) Mol. Med. 2, 143–149]. The l-dopachrome methyl ester tautomerase activity of human liver MIF was not inhibited by a variety of glutathione S-conjugates, eicosanoids or glucocorticoids but was very sensitive to inhibition by haematin (IC50 100–200 nM). The inhibition was non-competitive and showed positive co-operativity (h = 5.8). Similar sensitivity to haematin was obtained with purified recombinant human MIF. The sensitivity of MIF to haematin is approx. 1000-fold greater than for any previously described ligands, and is within its physiological range. Therefore the interaction is likely to be important in modulating the function of MIF in the initiation of immune responses.

scholarly journals High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

2016 ◽  
Vol 113 (8) ◽  
pp. E997-E1005 ◽  
Author(s):  
Thierry Roger ◽  
Anina Schneider ◽  
Manuela Weier ◽  
Fred C. G. J. Sweep ◽  
Didier Le Roy ◽  
...  
Keyword(s):  
Immune Responses ◽  
Migration Inhibitory Factor ◽  
Neonatal Sepsis ◽  
Defense Mechanisms ◽  
Macrophage Migration Inhibitory Factor ◽  
Severe Infection ◽  
Mechanistic Explanation ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Newborn Mice

The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.

scholarly journals Recombinant Mycobacterium smegmatis delivering a fusion protein of human macrophage migration inhibitory factor (MIF) and IL-7 exerts an anticancer effect by inducing an immune response against MIF in a tumor-bearing mouse model

2021 ◽  
Vol 9 (8) ◽  
pp. e003180
Author(s):  
Hyein Jeong ◽  
So-Young Lee ◽  
Hyejun Seo ◽  
Bum-Joon Kim
Keyword(s):  
Immune Response ◽  
Mouse Model ◽  
Immune Responses ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Tumor Bearing Mouse ◽  
Anticancer Effect ◽  
Tumor Bearing

BackgroundMacrophage migration inhibitory factor (MIF) is a pleotropic inflammatory cytokine that is overexpressed in a number of cancer types including most types of human cancer. Inhibition of MIF signaling can restore anticancer immune responses in tumor microenvironments. In this study, we aimed to develop a therapeutic vaccine capable of inhibiting tumor development by inducing anti-MIF immune responses.MethodsWe introduced a recombinant Mycobacterium smegmatis (rSmeg-hMIF-hIL-7) vaccine that could deliver a fusion protein of human macrophage migration inhibitory factor (MIF) and interleukin 7, which could act as a target antigen and as an adjuvant of cancer vaccine, respectively. We checked the anticancer potential of the vaccine in a tumor-bearing mouse model.ResultsWe found that rSmeg-hMIF-hIL-7 showed enhanced oncolytic activity compared with PBS, BCG or Smeg in MC38-bearing mice, and there was an increase in the humoral and cell-mediated immune responses against MIF. rSmeg-hMIF-hIL-7 can also induce a neutralizing effect regarding MIF tautomerase activity in the serum of vaccinated mice. We also found downregulation of MIF, CD74, and CD44, which are related to the MIF signaling pathway and PI3K/Akt and MMP2/9 signaling, which are regulated by MIF in the tumor tissue of rSmeg-hMIF-hIL-7-vaccinated mice, suggesting a significant role of the anti-MIF immune response to rSmeg-hMIF-hIL-7 in its anticancer effect. In addition, rSmeg-hMIF-hIL-7 treatment led to enhanced activation of CD4+ and CD8+ T cells in the tumor regions of vaccinated mice, also contributing to the anticancer effect. This trend was also found in LLC-bearing and PanO2-bearing mouse models. In addition, rSmeg-hMIF-hIL-7 treatment exerted an enhanced anticancer effect with one of the immune checkpoint inhibitors, the anti-PD-L1 antibody, in a tumor-bearing mouse model.ConclusionsIn conclusion, our data showed that rSmeg-hMIF-hIL-7 exerts a strong antitumor immune response in mice, possibly by inhibiting the MIF-dependent promotion of tumorigenesis by the anti-MIF immune response and via enhanced cytotoxic T cell recruitment into tumor microenvironments. We also found that it also exerted an enhanced anticancer effect with immune checkpoint inhibitors. These results suggest that rSmeg-hMIF-hIL-7 is a potential adjuvant for cancer immunotherapy. This is the first report to prove anticancer potential of immunotherapeutic vaccine targeting immune response against MIF.

scholarly journals Functional Characterization of the Plasmodium falciparum and P. berghei Homologues of Macrophage Migration Inhibitory Factor

2006 ◽  
Vol 75 (3) ◽  
pp. 1116-1128 ◽  
Author(s):  
Kevin D. Augustijn ◽  
Robert Kleemann ◽  
Joanne Thompson ◽  
Teake Kooistra ◽  
Carina E. Crawford ◽  
...  
Keyword(s):  
Immune Responses ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Functional Characterization ◽  
Inhibitory Factor ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Macrophage Migration ◽  
Human Embryonic Kidney Cells

ABSTRACT Macrophage migration inhibitory factor (MIF) is a mammalian cytokine that participates in innate and adaptive immune responses. Homologues of mammalian MIF have been discovered in parasite species infecting mammalian hosts (nematodes and malaria parasites), which suggests that the parasites express MIF to modulate the host immune response upon infection. Here we report the first biochemical and genetic characterization of a Plasmodium MIF (PMIF). Like human MIF, histidine-tagged purified recombinant PMIF shows tautomerase and oxidoreductase activities (although the activities are reduced compared to those of histidine-tagged human MIF) and efficiently inhibits AP-1 activity in human embryonic kidney cells. Furthermore, we found that Plasmodium berghei MIF is expressed in both a mammalian host and a mosquito vector and that, in blood stages, it is secreted into the infected erythrocytes and released upon schizont rupture. Mutant P. berghei parasites lacking PMIF were able to complete the entire life cycle and exhibited no significant changes in growth characteristics or virulence features during blood stage infection. However, rodent hosts infected with knockout parasites had significantly higher numbers of circulating reticulocytes. Our results suggest that PMIF is produced by the parasite to influence host immune responses and the course of anemia upon infection.

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