A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

Bai, Fengwei; Asojo, Oluwatoyin A.; Cirillo, Pier F.; Ciustea, Mihai; Ledizet, Michel; Aristoff, Paul A.; Leng, Lin; Koski, Raymond A.; Powell, Thomas; Bucala, Richard; Anthony, Karen G.

doi:10.1074/jbc.m112.385583

Cited by 60 publications

(79 citation statements)

References 73 publications

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“…Our finding that EhMIF induced IL-6 secretion is consistent with previous studies of MIF homologs (16,17,25,(40)(41)(42). IL-6 is a proinflammatory cytokine, and its main sources in the intestine are macrophages.…”

Section: Fig 3 Ehmif Immunomodulates Macrophages (A)supporting

confidence: 82%

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

et al. 2014

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bThe host inflammatory response contributes to the tissue damage that occurs during amebic colitis, with tumor necrosis factor alpha (TNF-␣) being a key mediator of the gut inflammation observed. Mammalian macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the exacerbation of a wide range of inflammatory diseases, including colitis. We identified a MIF gene homolog in the Entamoeba histolytica genome, raising the question of whether E. histolytica MIF (EhMIF) has proinflammatory activity similar to that of mammalian MIF. In this report, we describe the first functional characterization of EhMIF. Antibodies were prepared against recombinantly expressed EhMIF and used to demonstrate that EhMIF is expressed as a 12-kDa protein localized to the cytoplasm of trophozoites. In a manner similar to that of mammalian MIF, EhMIF interacted with the MIF receptor CD74 and bound to macrophages. EhMIF induced interleukin-6 (IL-6) production. In addition, EhMIF enhanced TNF-␣ secretion by amplifying TNF-␣ production by lipopolysaccharide (LPS)-stimulated macrophages and by inhibiting the glucocorticoid-mediated suppression of TNF-␣ secretion. EhMIF was expressed during human infection, as evidenced by the presence of anti-EhMIF antibodies in the sera of children living in an area where E. histolytica infection is endemic. Anti-EhMIF antibodies did not cross-react with human MIF. The ability of EhMIF to modulate host macrophage function may promote an exaggerated proinflammatory immune response and contribute to the tissue damage seen in amebic colitis.

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Section: Fig 3 Ehmif Immunomodulates Macrophages (A)supporting

confidence: 82%

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

et al. 2014

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“…7e). We next blocked MIF/CD74 interaction by injecting, into the ventricular cavity of E14.5 embryos, the allosteric MIF inhibitor p425 (1 ml, 0.5 mM), a molecule known to interfere with binding of MIF to the CD74 receptor 41 . Because p425 shows a brilliant blue tint in colour, we efficiently monitored its brain penetration.…”

Section: Resultsmentioning

confidence: 99%

“…For blocking of Cxc12/CxcR4 interaction, 1 ml of AMD3100 solution (12.6 mM; Sigma) or PBS was injected into the lateral ventricle at E12.5 and the embryos were left to develop in utero for 20 h. For blocking MIF/CD74 interaction, 1 ml of p425 (ref. 41; 0.5 mM) or PBS was injected in the lateral ventricle of E14.5 and the embryos were left to develop in utero until E16.5.…”

Section: E145mentioning

confidence: 99%

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

Arnò¹,

Grassivaro²,

Rossi³

et al. 2014

Nat Commun

187

173

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Microglia are observed in the early developing forebrain and contribute to the regulation of neurogenesis through still unravelled mechanisms. In the developing cerebral cortex, microglia cluster in the ventricular/subventricular zone (VZ/SVZ), a region containing Cxcl12-expressing basal progenitors (BPs). Here we show that the ablation of BP as well as genetic loss of Cxcl12 affect microglia recruitment into the SVZ. Ectopic Cxcl12 expression or pharmacological blockage of CxcR4 further supports that Cxcl12/CxcR4 signalling is involved in microglial recruitment during cortical development. Furthermore, we found that cell death in the developing forebrain triggers microglial proliferation and that this is mediated by the release of macrophage migration inhibitory factor (MIF). Finally, we show that the depletion of microglia in mice lacking receptor for colony-stimulating factor-1 (Csf-1R) reduces BPs into the cerebral cortex.

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“…The PB cytokine profile was unique to that of ALI with the most abundant cytokines in airway cast homogenates being proinflammatory, including MIF, CXCL8, and IL-16. MIF has been recognized for its ability to amplify inflammation and, interestingly, MIF and CXCL8 are known inflammatory cytokines of cystic fibrosis and asthma, respectively (22,23,47,48). Less is known about IL-16 but it, like CXCL8, has been associated with asthma (49).…”

Section: Original Articlementioning

confidence: 99%

“…MIF was also detected in the proteome and is recognized as a potent initiator of inflammation that is elevated in a number of inflammatory diseases including asthma (22).…”

Section: Cytokine Profile Of Plastic Bronchitis Casts Is Proinflammatorymentioning

confidence: 99%

Immunophenotyping and Protein Profiling of Fontan-associated Plastic Bronchitis Airway Casts

et al. 2013

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Rationale: Plastic bronchitis (PB) is a rare and deadly condition that is characterized by the formation of airway casts. It most frequently occurs in children with underlying congenital heart disease that has been surgically palliated by the Fontan procedure. The Fontan circulation results in above-normal central venous pressure, and it has been hypothesized that the formation of airway casts is due to lymph leak. Knowledge of plastic bronchitis pathogenesis is poor and stems mostly from published case reports.Objectives: To garner information about cast pathogenesis by characterizing inflammatory cell phenotypes in existing formalin-preserved, paraffin-embedded samples and generating protein and cytokine-chemokine profiles of airway cast homogenates.Methods: We used immunofluorescence confocal microscopy, state-of-the-science proteomics, and a cytokine array assay to immunophenotype cellular content and to generate protein and cytokine profiles of plastic bronchitis airway casts, respectively.Measurements and Main Results: Neutrophils, eosinophils, macrophages, and B lymphocytes were identified in cast samples; there were notably fewer T lymphocytes. Fibrin(ogen) was an abundant protein in the cast proteome. Histone H4 was also abundant, and immunofluorescence microscopy demonstrated it to be mostly extracellular. The cytokine profile of plastic bronchitis casts was proinflammatory.Conclusions: Plastic bronchitis airway casts from children with Fontan physiology are composed of fibrin and are cellular and inflammatory in nature, providing evidence that their formation cannot be explained simply by lymph leak into the airways. Consequences of cellular necrosis including extracellular histones and the apparent low number of T cells indicate that a derangement in inflammation resolution likely contributes to cast formation.

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A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

Cited by 60 publications

References 73 publications

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

Immunophenotyping and Protein Profiling of Fontan-associated Plastic Bronchitis Airway Casts

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