Macrophage migration inhibitory factor

Structure

Macrophage migration inhibitory factor assembles into a trimer composed of three identical subunits. Each of these monomers contain two antiparallel alpha helices and a four-stranded beta sheet. The monomers surround a central channel with 3-fold rotational symmetry.

MIF contains two motifs with catalytic activity. The first is a 27 amino acid motif located at the N-terminus functions as a phenylpyruvate tautomerase that can catalyze the conversion of 2-carboxy-2,3-dihydroindole-5,6-quinone (dopachrome) into 5,6-dihydroxyindole-2-carboxylic acid (DHICA). MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.

Mechanism of action

MIF binds to CD74, inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation. In addition to ERK, stimulation of CD74 activates other signaling pathways such PI3K-Akt, NF-κB, and AMP-activated protein kinase (AMPK) pathways.

Function

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation. MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids. This lymphokine and the JAB1 protein form a complex in the cytosol near the peripheral plasma membrane, which may indicate a role in integrin signaling pathways.

Cytokines play an important role in promoting wound healing and tissue repair. Cell injury results in MIF release which then interacts with CD74. MIF-CD74 signaling activates pro-survival and proliferative pathways that protects the host during injury.

Interactions

Macrophage migration inhibitory factor has been reported to interact with:

• BNIPL,
• CD74,
• COPS5,
• CXCR4, and
• RPS19.

Clinical significance

MIF is a potential drug target for sepsis, rheumatoid arthritis, and cancer.

Parasite-produced MIF homologs

Multiple protozoan parasites produce homologs MIF that have similar inflammatory functions to human MIF, and play a role in their pathogenesis, invasion and immune evasion. A preclinical study showed that blocking parasite MIF improves outcome in severe protozoan infections. Examples of protozoans with MIF homologs that have been reported:

• Entamoeba histolytica,
• Plasmodium falciparum,
• Toxoplasma gondii,
• Leishmania,
• Trichomonas vaginalis.

References

References

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