Macrophage migration inhibitory factor

MIF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CA7, 1CGQ, 1GCZ, 1GD0, 1GIF, 1LJT, 1MIF, 1P1G, 2OOH, 2OOW, 2OOZ, 3B9S, 3CE4, 3DJH, 3DJI, 3HOF, 3IJG, 3IJJ, 3JSF, 3JSG, 3JTU, 3L5P, 3L5R, 3L5S, 3L5T, 3L5U, 3L5V, 3SMB, 3SMC, 3U18, 4ETG, 4EUI, 4EVG, 4F2K, 4GRN, 4GRO, 4GRP, 4GRQ, 4GRR, 4GRU, 3WNR, 3WNS, 3WNT, 4K9G, 4OSF, 4OYQ, 4P01, 4P0H, 4WR8, 4WRB, 4PKZ, 4PLU, 4TRF, 4TRU, 4XX7, 4XX8, 5BS9, 5BSC, 5BSI, 5EIZ, 5HVV, 5CG4, 5J7Q, 5BSJ, 5HVT, 4PKK, 5B4O, 5HVS, 5J7P
Identifiers
Aliases	MIF, GIF, GLIF, Mmacrophage migration inhibitory factor (glycosylation-inhibiting factor)
External IDs	OMIM: 153620 MGI: 96982 HomoloGene: 55655 GeneCards: MIF
EC number	5.3.3.12
Gene ontology Molecular function • cytokine activity • isomerase activity • protein binding • chemoattractant activity • phenylpyruvate tautomerase activity • receptor binding • dopachrome isomerase activity • cytokine receptor binding Cellular component • cytoplasm • vesicle • myelin sheath • nucleoplasm • extracellular fluid • extracellular region • cell surface • extracellular exosome Biological process • positive regulation of protein phosphorylation • negative regulation of cellular protein metabolic process • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • positive regulation of MAP kinase activity • carboxylic acid metabolic process • positive regulation of chemokine (C-X-C motif) ligand 2 production • immune system process • positive regulation of fibroblast proliferation • negative regulation of cell aging • positive regulation of cytokine secretion • DNA damage response, signal transduction by p53 class mediator • negative regulation of apoptotic process • negative regulation of mature B cell apoptotic process • negative regulation of gene expression • positive regulation of peptidyl-serine phosphorylation • protein homotrimerization • negative regulation of cell cycle arrest • positive regulation of lipopolysaccharide-mediated signaling pathway • cell aging • cell surface receptor signaling pathway • negative regulation of DNA damage response, signal transduction by p53 class mediator • regulation of cell proliferation • positive regulation of arachidonic acid secretion • positive regulation of B cell proliferation • positive regulation of ERK1 and ERK2 cascade • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of prostaglandin secretion involved in immune response • prostaglandin biosynthetic process • innate immune response • negative regulation of myeloid cell apoptotic process • inflammatory response • cell proliferation • positive regulation of phosphorylation • positive regulation of myeloid leukocyte cytokine production involved in immune response • leukocyte migration • regulation of macrophage activation • positive regulation of protein kinase A signaling • positive chemotaxis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4282	17319
Ensembl	n/a	ENSMUSG00000033307
UniProt	P14174	P34884
RefSeq (mRNA)	NM_002415	NM_010798
RefSeq (protein)	NP_002406.1 NP_002406.1	NP_034928.1
Location (UCSC)	Chr 22: 23.89 – 23.9 Mb	Chr 10: 75.86 – 75.86 Mb
PubMed search	[1]	[2]
Wikidata

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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.^[3][4] MIF is an important regulator of innate immunity.^[5]

Bacterial antigens stimulate white blood cells to release MIF into the blood stream.^[6] 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.^[7]

Structure

Macrophage migration inhibitory factor (MIF)
Identifiers
Symbol	MIF
Pfam	PF01187
InterPro	IPR001398
PROSITE	PDOC00892
SCOP	1mif
SUPERFAMILY	1mif
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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.^[8][9]

Enzymatic activity

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).^[10][11] MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.^[12]

Function

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.^[13][14][15] MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.^[15][16][17] 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.^[18]

Mechanism of action

MIF binds to CD74,^[19] inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.^[20]

Interactions

Macrophage migration inhibitory factor has been reported to interact with:

• BNIPL,^[21]
• CD74,^{[22][23][24][25][26]}
• COPS5,^[27]
• CXCR4,^[28][29][30] and
• RPS19.^[31]

Clinical significance

MIF is an inflammatory mediator associated with rheumatoid arthritis (RA) severity.^[32][33][34] MIF protein levels are increased in the plasma of people with schizophrenia, including people in the early stages of the illness, but the clinical significance of this has not been determined.^[35][36]

It has also been shown to induce changes in the heart during sepsis.^[37]

Evidence suggests that there is a correlation between MIF production and metastatic potential in colorectal cancer.^[38]

In addition, it was reported that there is an increased MIF production in Alzheimer's disease and mild cognitive impairment.^[39]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. 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". Proc. Natl. Acad. Sci. U.S.A. 86 (19): 7522–6. doi:10.1073/pnas.86.19.7522. PMC 298097. PMID 2552447.
4. 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.
5. Calandra T, Roger T (October 2003). "Macrophage migration inhibitory factor: a regulator of innate immunity". Nat. Rev. Immunol. 3 (10): 791–800. doi:10.1038/nri1200. PMID 14502271.
6. Barret, James (1980). Basic Immunology and its Medical Application (2 ed.). St.Louis: The C.V. Mosby Company. ISBN 0-8016-0495-8.
7. Larson DF, Horak K (2006). "Macrophage migration inhibitory factor: controller of systemic inflammation". Crit Care. 10 (2): 138. doi:10.1186/cc4899. PMC 1550887. PMID 16677407.
8. Sun HW, Bernhagen J, Bucala R, Lolis E (May 1996). "Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor". Proc. Natl. Acad. Sci. U.S.A. 93 (11): 5191–6. doi:10.1073/pnas.93.11.5191. PMC 39220. PMID 8643551.
9. Al-Abed Y, VanPatten S (January 2011). "MIF as a disease target: ISO-1 as a proof-of-concept therapeutic". Future Med Chem. 3 (1): 45–63. doi:10.4155/fmc.10.281. PMID 21428825.
10. 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". Mol. Med. 2 (1): 143–9. PMC 2230029. PMID 8900542.
11. 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". J. Clin. Endocrinol. Metab. 95 (12): E403–12. doi:10.1210/jc.2010-0417. PMID 20829186.
12. Thiele M, Bernhagen J (2005). "Link between macrophage migration inhibitory factor and cellular redox regulation". Antioxid. Redox Signal. 7 (9-10): 1234–48. doi:10.1089/ars.2005.7.1234. PMID 16115028.
13. Leng L, Bucala R (February 2006). "Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptor". Cell Res. 16 (2): 162–8. doi:10.1038/sj.cr.7310022. PMID 16474429.
14. Chen PF, Luo YL, Wang W, Wang JX, Lai WY, Hu SM, Cheng KF, Al-Abed Y (2010). "ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma". Mol. Med. 16 (9-10): 400–8. doi:10.2119/molmed.2009.00128. PMC 2935952. PMID 20485865.
15. Takahashi K, Koga K, Linge HM, Zhang Y, Lin X, Metz CN, Al-Abed Y, Ojamaa K, Miller EJ (2009). "Macrophage CD74 contributes to MIF-induced pulmonary inflammation". Respir. Res. 10 (1): 33. doi:10.1186/1465-9921-10-33. PMC 2681459. PMID 19413900.
16. Flaster H, Bernhagen J, Calandra T, Bucala R (June 2007). "The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity". Mol. Endocrinol. 21 (6): 1267–80. doi:10.1210/me.2007-0065. PMID 17389748.
17. Al-Abed Y, Metz CN, Cheng KF, Aljabari B, VanPatten S, Blau S, Lee H, Ochani M, Pavlov VA, Coleman T, Meurice N, Tracey KJ, Miller EJ (May 2011). "Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity". Proc. Natl. Acad. Sci. U.S.A. 108 (20): 8224–7. doi:10.1073/pnas.1017624108. PMC 3100930. PMID 21536912.
18. "Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor)".
19. Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R (October 1993). "MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia". Nature. 365 (6448): 756–9. doi:10.1038/365756a0. PMID 8413654.
20. Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R (October 2006). "CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex". Immunity. 25 (4): 595–606. doi:10.1016/j.immuni.2006.08.020. PMC 3707630. PMID 17045821.
21. Shen L, Hu J, Lu H, Wu M, Qin W, Wan D, Li YY, Gu J (April 2003). "The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER". FEBS Lett. 540 (1-3): 86–90. doi:10.1016/S0014-5793(03)00229-1. PMID 12681488.
22. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R (June 2003). "MIF signal transduction initiated by binding to CD74". J. Exp. Med. 197 (11): 1467–76. doi:10.1084/jem.20030286. PMC 2193907. PMID 12782713.
23. Bacher M, Deuster O, Aljabari B, Egensperger R, Neff F, Jessen F, Popp J, Noelker C, Reese JP, Al-Abed Y, Dodel R (March 2010). "The role of macrophage migration inhibitory factor in Alzheimer's disease". Mol. Med. 16 (3-4): 116–21. doi:10.2119/molmed.2009.00123. PMC 2829616. PMID 20200619.
24. Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY (December 2009). "[Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system]". Nan Fang Yi Ke Da Xue Xue Bao (in Chinese). 29 (12): 2383–6, 2390. PMID 20034881.
25. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J (February 2010). "Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats". Pain. 148 (2): 275–83. doi:10.1016/j.pain.2009.11.011. PMID 20005040.
26. Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, Waters AP, Wilkinson AJ (December 2009). "The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei". Protein Sci. 18 (12): 2578–91. doi:10.1002/pro.263. PMC 2798171. PMID 19827093.
27. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J (November 2000). "Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1". Nature. 408 (6809): 211–6. doi:10.1038/35041591. PMID 11089976.
28. Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, Bucala R, Weber C, Bernhagen J (September 2009). "A functional heteromeric MIF receptor formed by CD74 and CXCR4". FEBS Lett. 583 (17): 2749–57. doi:10.1016/j.febslet.2009.07.058. PMC 2911026. PMID 19665027.
29. Schrader J, Deuster O, Rinn B, Schulz M, Kautz A, Dodel R, Meyer B, Al-Abed Y, Balakrishnan K, Reese JP, Bacher M (2009). "Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown". BMC Cancer. 9: 464. doi:10.1186/1471-2407-9-464. PMC 2810303. PMID 20038293.
30. Stosic-Grujicic S, Stojanovic I, Maksimovic-Ivanic D, Momcilovic M, Popadic D, Harhaji L, Miljkovic D, Metz C, Mangano K, Papaccio G, Al-Abed Y, Nicoletti F (June 2008). "Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus". J. Cell. Physiol. 215 (3): 665–75. doi:10.1002/jcp.21346. PMID 18064633.
31. Filip AM, Klug J, Cayli S, Fröhlich S, Henke T, Lacher P, Eickhoff R, Bulau P, Linder M, Carlsson-Skwirut C, Leng L, Bucala R, Kraemer S, Bernhagen J, Meinhardt A (March 2009). "Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function". J. Biol. Chem. 284 (12): 7977–85. doi:10.1074/jbc.M808620200. PMC 2658091. PMID 19155217.
32. Bifulco C, McDaniel K, Leng L, Bucala R (2008). "Tumor growth-promoting properties of macrophage migration inhibitory factor". Curr. Pharm. Des. 14 (36): 3790–801. doi:10.2174/138161208786898608. PMID 19128232.
33. Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A (July 2009). "Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage migration inhibitory factor: involvement of novel kinase signaling pathways". Endocrinology. 150 (7): 3128–37. doi:10.1210/en.2008-1088. PMC 2703510. PMID 19299454.
34. Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J (April 2002). "Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease". Microbes Infect. 4 (4): 449–60. doi:10.1016/S1286-4579(02)01560-5. PMID 11932196.
35. Pearce B, Weis K, DiGirolamo A, Bremner J, Miller A, Wang X (2003). "MIF, a proinflammatory cytokine and anti-glucocorticoid, is elevated in schizophrenia". European Archives Psychiatry Clinical Neurosciences. 253: 265. doi:10.1007/s00406-003-0451-4.
36. Chan MK, Krebs MO, Cox D, et al. (2015). "Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset". Transl Psychiatry. 5: e601. doi:10.1038/tp.2015.91.
37. Lin X, Sakuragi T, Metz CN, Ojamaa K, Skopicki HA, Wang P, Al-Abed Y, Miller EJ (December 2005). "Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis". Shock. 24 (6): 556–63. doi:10.1097/01.shk.0000183238.70374.a8. PMID 16317387.
38. He XX, Chen K, Yang J, Li XY, Gan HY, Liu CY, Coleman TR, Al-Abed Y (2009). "Macrophage migration inhibitory factor promotes colorectal cancer". Mol. Med. 15 (1-2): 1–10. doi:10.2119/molmed.2008.00107. PMC 2581606. PMID 19009023.
39. Popp J, Bacher M, Kölsch H, Noelker C, Deuster O, Dodel R, Jessen F (2009). "Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer's disease.". J Psychiatr Res. 43 (8): 749–753. doi:10.1016/j.jpsychires.2008.10.006. PMID 19038405.