Macrophage migration inhibitory factor

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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.[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]


Macrophage migration inhibitory factor (MIF)

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

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]


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

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]


Macrophage migration inhibitory factor has been reported to interact with:

Clinical significance

MIF is an inflammatory mediator associated with rheumatoid arthritis (RA) severity.[30][31][32] 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.[33][34] Macrophage migration inhibitory factor is also a potential drug target for sepsis, rheumatoid arthritis, and cancer.[35] It has also been shown to induce changes in the heart during sepsis.[36]

Evidence suggests that there is a correlation between MIF production and metastatic potential in colorectal cancer.[37]

It has been reported that there is increased MIF production in Alzheimer's disease and mild cognitive impairment.[38] It has further been reported that this enzyme, in Alzheimer's disease, undergoes glycation and oxidation, inhibiting its activity.[39]


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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.
  10. Thiele M, Bernhagen J (2005). "Link between macrophage migration inhibitory factor and cellular redox regulation". Antioxidants & Redox Signaling. 7 (9–10): 1234–48. doi:10.1089/ars.2005.7.1234. PMID 16115028.
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  12. 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". Molecular Medicine. 16 (9–10): 400–8. doi:10.2119/molmed.2009.00128. PMC 2935952. PMID 20485865.
  13. 13.0 13.1 Takahashi K, Koga K, Linge HM, Zhang Y, Lin X, Metz CN, Al-Abed Y, Ojamaa K, Miller EJ (May 2009). "Macrophage CD74 contributes to MIF-induced pulmonary inflammation". Respiratory Research. 10 (1): 33. doi:10.1186/1465-9921-10-33. PMC 2681459. PMID 19413900.
  14. Flaster H, Bernhagen J, Calandra T, Bucala R (June 2007). "The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity". Molecular Endocrinology. 21 (6): 1267–80. doi:10.1210/me.2007-0065. PMID 17389748.
  15. 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". Proceedings of the National Academy of Sciences of the United States of America. 108 (20): 8224–7. doi:10.1073/pnas.1017624108. PMC 3100930. PMID 21536912.
  16. "Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor)".
  17. 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.
  18. 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.
  19. 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 Letters. 540 (1–3): 86–90. doi:10.1016/S0014-5793(03)00229-1. PMID 12681488.
  20. 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". The Journal of Experimental Medicine. 197 (11): 1467–76. doi:10.1084/jem.20030286. PMC 2193907. PMID 12782713.
  21. 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". Molecular Medicine. 16 (3–4): 116–21. doi:10.2119/molmed.2009.00123. PMC 2829616. PMID 20200619.
  22. 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 = Journal of Southern Medical University (in Chinese). 29 (12): 2383–6, 2390. PMID 20034881.
  23. 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.
  24. 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 Science. 18 (12): 2578–91. doi:10.1002/pro.263. PMC 2798171. PMID 19827093.
  25. 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.
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  27. Schrader J, Deuster O, Rinn B, Schulz M, Kautz A, Dodel R, Meyer B, Al-Abed Y, Balakrishnan K, Reese JP, Bacher M (December 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.
  28. 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". Journal of Cellular Physiology. 215 (3): 665–75. doi:10.1002/jcp.21346. PMID 18064633.
  29. 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". The Journal of Biological Chemistry. 284 (12): 7977–85. doi:10.1074/jbc.M808620200. PMC 2658091. PMID 19155217.
  30. Bifulco C, McDaniel K, Leng L, Bucala R (2008). "Tumor growth-promoting properties of macrophage migration inhibitory factor". Current Pharmaceutical Design. 14 (36): 3790–801. doi:10.2174/138161208786898608. PMID 19128232.
  31. 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.
  32. 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 and Infection. 4 (4): 449–60. doi:10.1016/S1286-4579(02)01560-5. PMID 11932196.
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  34. Chan MK, Krebs MO, Cox D, Guest PC, Yolken RH, Rahmoune H, Rothermundt M, Steiner J, Leweke FM, van Beveren NJ, Niebuhr DW, Weber NS, Cowan DN, Suarez-Pinilla P, Crespo-Facorro B, Mam-Lam-Fook C, Bourgin J, Wenstrup RJ, Kaldate RR, Cooper JD, Bahn S (July 2015). "Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset". Translational Psychiatry. 5: e601. doi:10.1038/tp.2015.91. PMID 26171982.
  35. Bloom J, Sun S, Al-Abed Y (2016). "MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development". Expert Opinion on Therapeutic Targets. 20 (12): 1463–1475. doi:10.1080/14728222.2016.1251582. PMID 27762152.
  36. 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.
  37. 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". Molecular Medicine. 15 (1–2): 1–10. doi:10.2119/molmed.2008.00107. PMC 2581606. PMID 19009023.
  38. Popp J, Bacher M, Kölsch H, Noelker C, Deuster O, Dodel R, Jessen F (May 2009). "Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer's disease". Journal of Psychiatric Research. 43 (8): 749–53. doi:10.1016/j.jpsychires.2008.10.006. PMID 19038405.
  39. Kassaar O, Pereira Morais M, Xu S, Adam EL, Chamberlain RC, Jenkins B, James TD, Francis PT, Ward S, Williams RJ, van den Elsen J (February 2017). "Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer's Disease". Scientific Reports. 7 (42874): 42874. doi:10.1038/srep42874. PMID 28230058.