Macrophage migration inhibitory factor

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Macrophage migration inhibitory factor (MIF)
Identifiers
SymbolMIF
PfamPF01187
InterProIPR001398
PROSITEPDOC00892
SCOP1mif
SUPERFAMILY1mif

Macrophage migration inhibitory factor (MIF or MMIF), also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase is a protein that in humans is encoded by the MIF gene.[1][2] MIF is an important regulator of innate immunity.[3]

Bacterial antigens stimulate white blood cells to release MIF into the blood stream.[4] The circulating MIF binds to CD74 on other immune cells to trigger an acute immune response. Hence, MIF is classified as an inflammatory cytokine. Furthermore, glucocorticoids also stimulate white blood cells to release MIF and hence MIF partially counteracts the inhibitory effects that glucocorticoids have on the immune system. Finally trauma activates the anterior pituitary gland to release MIF.[5]

Structure[edit]

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.[6][7]

Enzymatic activity[edit]

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).[8][9] MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.[10]

Function[edit]

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.[11][12][13] MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.[13][14][15] 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.[16]

Mechanism of action[edit]

MIF binds to CD74,[17] inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.[18]

Interactions[edit]

Macrophage migration inhibitory factor has been reported to interact with:

Clinical significance[edit]

MIF is a potential drug target for sepsis, rheumatoid arthritis, and cancer.[31][32]

Parasite-produced MIF homologs[edit]

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.[33] Examples of protozoans with MIF homologs that have been reported:

References[edit]

  1. ^ Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR (October 1989). "Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor". Proceedings of the National Academy of Sciences of the United States of America. 86 (19): 7522–6. doi:10.1073/pnas.86.19.7522. PMC 298097. PMID 2552447.
  2. ^ Kozak CA, Adamson MC, Buckler CE, Segovia L, Paralkar V, Wistow G (June 1995). "Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes". Genomics. 27 (3): 405–11. doi:10.1006/geno.1995.1070. PMID 7558020.
  3. ^ Calandra T, Roger T (October 2003). "Macrophage migration inhibitory factor: a regulator of innate immunity". Nature Reviews. Immunology. 3 (10): 791–800. doi:10.1038/nri1200. PMID 14502271.
  4. ^ Barret, James (1980). Basic Immunology and its Medical Application (2 ed.). St.Louis: The C.V. Mosby Company. ISBN 978-0-8016-0495-9.
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  6. ^ Sun HW, Bernhagen J, Bucala R, Lolis E (May 1996). "Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5191–6. doi:10.1073/pnas.93.11.5191. PMC 39220. PMID 8643551.
  7. ^ Al-Abed Y, VanPatten S (January 2011). "MIF as a disease target: ISO-1 as a proof-of-concept therapeutic". Future Medicinal Chemistry. 3 (1): 45–63. doi:10.4155/fmc.10.281. PMID 21428825.
  8. ^ Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H (January 1996). "The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction". Molecular Medicine. 2 (1): 143–9. PMC 2230029. PMID 8900542.
  9. ^ Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A (December 2010). "Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways". The Journal of Clinical Endocrinology and Metabolism. 95 (12): E403–12. doi:10.1210/jc.2010-0417. PMID 20829186.
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