Macrophage migration inhibitory factor explained

Symbol:MIF
Macrophage migration inhibitory factor (MIF)
Pfam:PF01187
Interpro:IPR001398
Prosite:PDOC00892
Scop:1mif

Macrophage migration inhibitory factor (MIF), 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] The MIF protein superfamily also includes a second member with functionally related properties, the D-dopachrome tautomerase (D-DT).[4] CD74 is a surface receptor for MIF.[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 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]

Response to injury

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.[10]

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).[11] [12] MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.[13]

Function

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.[14] [15] [16] MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.[16] [17] [18] 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.[19]

Mechanism of action

MIF binds to CD74,[20] inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.[21] In addition to ERK, stimulation of CD74 activates other signaling pathways such PI3K-Akt, NF-κB, and AMP-activated protein kinase (AMPK) pathways.[22]

Interactions

Macrophage migration inhibitory factor has been reported to interact with:

Clinical significance

MIF is a potential drug target for sepsis, rheumatoid arthritis, and cancer.[36] [37]

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.[38] [39] A preclinical study showed that blocking parasite MIF improves outcome in severe protozoan infections.[40] Examples of protozoans with MIF homologs that have been reported:

Notes and References

  1. Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR . 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 . October 1989 . 2552447 . 298097 . 10.1073/pnas.86.19.7522 . 1989PNAS...86.7522W . free .
  2. Kozak CA, Adamson MC, Buckler CE, Segovia L, Paralkar V, Wistow G . 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 . June 1995 . 7558020 . 10.1006/geno.1995.1070 .
  3. Calandra T, Roger T . Macrophage migration inhibitory factor: a regulator of innate immunity . Nature Reviews. Immunology . 3 . 10 . 791–800 . October 2003 . 14502271 . 7097468 . 10.1038/nri1200 .
  4. Günther S, Fagone P, Jalce G, Atanasov AG, Guignabert C, Nicoletti F . Role of MIF and D-DT in immune-inflammatory, autoimmune, and chronic respiratory diseases: from pathogenic factors to therapeutic targets . Drug Discovery Today . 24 . 2 . 428–439 . February 2019 . 30439447 . 10.1016/j.drudis.2018.11.003 . 53562815 .
  5. Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair . Frontiers in Immunology . 11 . 1273 . 2020 . 32655566 . 10.3389/fimmu.2020.01273 . 7325688 . free .
  6. Book: Barret, James . 1980 . Basic Immunology and its Medical Application . 2 . St.Louis . The C.V. Mosby Company . 978-0-8016-0495-9 .
  7. Larson DF, Horak K . Macrophage migration inhibitory factor: controller of systemic inflammation . Critical Care . 10 . 2 . 138 . 2006 . 16677407 . 1550887 . 10.1186/cc4899 . free .
  8. Sun HW, Bernhagen J, Bucala R, Lolis E . 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 . May 1996 . 8643551 . 39220 . 10.1073/pnas.93.11.5191 . free .
  9. Al-Abed Y, VanPatten S . MIF as a disease target: ISO-1 as a proof-of-concept therapeutic . Future Medicinal Chemistry . 3 . 1 . 45–63 . January 2011 . 21428825 . 10.4155/fmc.10.281 .
  10. Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair . Frontiers in Immunology . 11 . 1273 . 2020 . 32655566 . 10.3389/fimmu.2020.01273 . 7325688 . free .
  11. Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H . The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction . Molecular Medicine . 2 . 1 . 143–9 . January 1996 . 8900542 . 2230029 . 10.1007/BF03402210 .
  12. Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A . 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 . December 2010 . 20829186 . 10.1210/jc.2010-0417 . free .
  13. Thiele M, Bernhagen J . Link between macrophage migration inhibitory factor and cellular redox regulation . Antioxidants & Redox Signaling . 7 . 9–10 . 1234–48 . 2005 . 16115028 . 10.1089/ars.2005.7.1234 .
  14. Leng L, Bucala R . Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptor . Cell Research . 16 . 2 . 162–8 . February 2006 . 16474429 . 10.1038/sj.cr.7310022 . free .
  15. Chen PF, Luo YL, Wang W, Wang JX, Lai WY, Hu SM, Cheng KF, Al-Abed Y . 6 . 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 . 2010 . 20485865 . 2935952 . 10.2119/molmed.2009.00128 .
  16. Takahashi K, Koga K, Linge HM, Zhang Y, Lin X, Metz CN, Al-Abed Y, Ojamaa K, Miller EJ . 6 . Macrophage CD74 contributes to MIF-induced pulmonary inflammation . Respiratory Research . 10 . 1 . 33 . May 2009 . 19413900 . 2681459 . 10.1186/1465-9921-10-33 . free .
  17. Flaster H, Bernhagen J, Calandra T, Bucala R . The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity . Molecular Endocrinology . 21 . 6 . 1267–80 . June 2007 . 17389748 . 10.1210/me.2007-0065 . free .
  18. 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 . 6 . 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 . May 2011 . 21536912 . 3100930 . 10.1073/pnas.1017624108 . 2011PNAS..108.8224A . free .
  19. Web site: Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor).
  20. Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R . 4321353 . 6 . MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia . Nature . 365 . 6448 . 756–9 . October 1993 . 8413654 . 10.1038/365756a0 . 1993Natur.365..756B .
  21. 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 . 6 . CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex . Immunity . 25 . 4 . 595–606 . October 2006 . 17045821 . 3707630 . 10.1016/j.immuni.2006.08.020 .
  22. Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair . Frontiers in Immunology . 11 . 1273 . 2020 . 32655566 . 10.3389/fimmu.2020.01273 . 7325688 . free .
  23. Shen L, Hu J, Lu H, Wu M, Qin W, Wan D, Li YY, Gu J . 6 . The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER . FEBS Letters . 540 . 1–3 . 86–90 . April 2003 . 12681488 . 10.1016/S0014-5793(03)00229-1 . free .
  24. Farr L, Ghosh S, Jiang N, Watanabe K, Parlak M, Bucala R, Moonah S . CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing . Cellular and Molecular Gastroenterology and Hepatology . 10 . 1 . 101–112 . 2020 . 32004754 . 10.1016/j.jcmgh.2020.01.009 . 7215244 .
  25. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R . 6 . MIF signal transduction initiated by binding to CD74 . The Journal of Experimental Medicine . 197 . 11 . 1467–76 . June 2003 . 12782713 . 2193907 . 10.1084/jem.20030286 .
  26. Bacher M, Deuster O, Aljabari B, Egensperger R, Neff F, Jessen F, Popp J, Noelker C, Reese JP, Al-Abed Y, Dodel R . 6 . The role of macrophage migration inhibitory factor in Alzheimer's disease . Molecular Medicine . 16 . 3–4 . 116–21 . March 2010 . 20200619 . 2829616 . 10.2119/molmed.2009.00123 .
  27. Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY . 6 . [Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system] . zh . Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University . 29 . 12 . 2383–6, 2390 . December 2009 . 20034881 .
  28. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J . 38141283 . Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats . Pain . 148 . 2 . 275–83 . February 2010 . 20005040 . 10.1016/j.pain.2009.11.011 .
  29. Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, Waters AP, Wilkinson AJ . 6 . The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei . Protein Science . 18 . 12 . 2578–91 . December 2009 . 19827093 . 2798171 . 10.1002/pro.263 .
  30. Ghosh S, Leaton LA, Farr L, Barfield A, Moonah S . Interaction between parasite-encoded JAB1/CSN5 and macrophage migration inhibitory factor proteins attenuates its proinflammatory function . Scientific Reports . 8 . 1 . 10241 . July 2018 . 29980718 . 6035221 . 10.1038/s41598-018-28625-1 . 2018NatSR...810241G .
  31. 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 . 205010648 . 6 . Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1 . Nature . 408 . 6809 . 211–6 . November 2000 . 11089976 . 10.1038/35041591 . 2000Natur.408..211K .
  32. Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, Bucala R, Weber C, Bernhagen J . 6 . A functional heteromeric MIF receptor formed by CD74 and CXCR4 . FEBS Letters . 583 . 17 . 2749–57 . September 2009 . 19665027 . 2911026 . 10.1016/j.febslet.2009.07.058 .
  33. Schrader J, Deuster O, Rinn B, Schulz M, Kautz A, Dodel R, Meyer B, Al-Abed Y, Balakrishnan K, Reese JP, Bacher M . 6 . Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown . BMC Cancer . 9 . 464 . December 2009 . 20038293 . 2810303 . 10.1186/1471-2407-9-464 . free .
  34. 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 . 6 . Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus . Journal of Cellular Physiology . 215 . 3 . 665–75 . June 2008 . 18064633 . 10.1002/jcp.21346 . 36047003 .
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