Macrophage migration inhibitory factor

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.{{cite journal | vauthors = Sun HW, Bernhagen J, Bucala R, Lolis E | title = Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5191–5196 | date = May 1996 | pmid = 8643551 | pmc = 39220 | doi = 10.1073/pnas.93.11.5191 | doi-access = free }}{{cite journal | vauthors = Al-Abed Y, VanPatten S | title = MIF as a disease target: ISO-1 as a proof-of-concept therapeutic | journal = Future Medicinal Chemistry | volume = 3 | issue = 1 | pages = 45–63 | date = January 2011 | pmid = 21428825 | doi = 10.4155/fmc.10.281 }}

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).{{cite journal | vauthors = Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H | title = The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction | journal = Molecular Medicine | location = Cambridge, Mass. | volume = 2 | issue = 1 | pages = 143–149 | date = January 1996 | pmid = 8900542 | pmc = 2230029 | doi = 10.1007/BF03402210 }}{{cite journal | vauthors = Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A | title = 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 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 95 | issue = 12 | pages = E403–E412 | date = December 2010 | pmid = 20829186 | doi = 10.1210/jc.2010-0417 | doi-access = free }} MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.{{cite journal | vauthors = Thiele M, Bernhagen J | title = Link between macrophage migration inhibitory factor and cellular redox regulation | journal = Antioxidants & Redox Signaling | volume = 7 | issue = 9–10 | pages = 1234–1248 | year = 2005 | pmid = 16115028 | doi = 10.1089/ars.2005.7.1234 }}

MIF binds to CD74,{{cite journal | vauthors = Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R | title = MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia | journal = Nature | volume = 365 | issue = 6448 | pages = 756–759 | date = October 1993 | pmid = 8413654 | doi = 10.1038/365756a0 | s2cid = 4321353 | bibcode = 1993Natur.365..756B }} inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.{{cite journal | vauthors = 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 | title = CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex | journal = Immunity | volume = 25 | issue = 4 | pages = 595–606 | date = October 2006 | pmid = 17045821 | pmc = 3707630 | doi = 10.1016/j.immuni.2006.08.020 }} In addition to ERK, stimulation of CD74 activates other signaling pathways such PI3K-Akt, NF-κB, and AMP-activated protein kinase (AMPK) pathways.

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.{{cite journal | vauthors = Leng L, Bucala R | title = Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptor | journal = Cell Research | volume = 16 | issue = 2 | pages = 162–168 | date = February 2006 | pmid = 16474429 | doi = 10.1038/sj.cr.7310022 | doi-access = free }}{{cite journal | vauthors = Chen PF, Luo YL, Wang W, Wang JX, Lai WY, Hu SM, Cheng KF, Al-Abed Y | title = ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma | journal = Molecular Medicine | location = Cambridge, Mass. | volume = 16 | issue = 9–10 | pages = 400–408 | year = 2010 | pmid = 20485865 | pmc = 2935952 | doi = 10.2119/molmed.2009.00128 }}{{cite journal | vauthors = Takahashi K, Koga K, Linge HM, Zhang Y, Lin X, Metz CN, Al-Abed Y, Ojamaa K, Miller EJ | title = Macrophage CD74 contributes to MIF-induced pulmonary inflammation | journal = Respiratory Research | volume = 10 | issue = 1 | pages = 33 | date = May 2009 | pmid = 19413900 | pmc = 2681459 | doi = 10.1186/1465-9921-10-33 | doi-access = free }} MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.{{cite journal | vauthors = Flaster H, Bernhagen J, Calandra T, Bucala R | title = The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 21 | issue = 6 | pages = 1267–1280 | date = June 2007 | pmid = 17389748 | doi = 10.1210/me.2007-0065 | doi-access = free }}{{cite journal | vauthors = 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 | title = Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 20 | pages = 8224–8227 | date = May 2011 | pmid = 21536912 | pmc = 3100930 | doi = 10.1073/pnas.1017624108 | bibcode = 2011PNAS..108.8224A | doi-access = free }} 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.{{cite web | title = Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor) | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4282 }}

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.

Macrophage migration inhibitory factor has been reported to interact with:

• BNIPL,{{cite journal | vauthors = Shen L, Hu J, Lu H, Wu M, Qin W, Wan D, Li YY, Gu J | title = The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER | journal = FEBS Letters | volume = 540 | issue = 1–3 | pages = 86–90 | date = April 2003 | pmid = 12681488 | doi = 10.1016/S0014-5793(03)00229-1 | doi-access = free | bibcode = 2003FEBSL.540...86S }}
• CD74,{{cite journal | vauthors = Farr L, Ghosh S, Jiang N, Watanabe K, Parlak M, Bucala R, Moonah S | title = CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing | journal = Cellular and Molecular Gastroenterology and Hepatology | volume = 10 | issue = 1 | pages = 101–112 | date = 2020 | pmid = 32004754 | pmc = 7215244 | doi = 10.1016/j.jcmgh.2020.01.009 }}{{cite journal | vauthors = Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R | title = MIF signal transduction initiated by binding to CD74 | journal = The Journal of Experimental Medicine | volume = 197 | issue = 11 | pages = 1467–1476 | date = June 2003 | pmid = 12782713 | pmc = 2193907 | doi = 10.1084/jem.20030286 }}{{cite journal | vauthors = Bacher M, Deuster O, Aljabari B, Egensperger R, Neff F, Jessen F, Popp J, Noelker C, Reese JP, Al-Abed Y, Dodel R | title = The role of macrophage migration inhibitory factor in Alzheimer's disease | journal = Molecular Medicine | location = Cambridge, Mass. | volume = 16 | issue = 3–4 | pages = 116–121 | date = March 2010 | pmid = 20200619 | pmc = 2829616 | doi = 10.2119/molmed.2009.00123 }}{{cite journal | vauthors = Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY | title = [Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system] | journal = Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University | volume = 29 | issue = 12 | pages = 2383–6, 2390 | date = December 2009 | pmid = 20034881 | language = zh }}{{cite journal | vauthors = Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J | title = Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats | journal = Pain | volume = 148 | issue = 2 | pages = 275–283 | date = February 2010 | pmid = 20005040 | doi = 10.1016/j.pain.2009.11.011 | s2cid = 38141283 }}{{cite journal | vauthors = Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, Waters AP, Wilkinson AJ | title = The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei | journal = Protein Science | volume = 18 | issue = 12 | pages = 2578–2591 | date = December 2009 | pmid = 19827093 | pmc = 2798171 | doi = 10.1002/pro.263 }}
• COPS5,{{cite journal | vauthors = Ghosh S, Leaton LA, Farr L, Barfield A, Moonah S | title = Interaction between parasite-encoded JAB1/CSN5 and macrophage migration inhibitory factor proteins attenuates its proinflammatory function | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 10241 | date = July 2018 | pmid = 29980718 | pmc = 6035221 | doi = 10.1038/s41598-018-28625-1 | bibcode = 2018NatSR...810241G }}{{cite journal | vauthors = 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 | title = Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1 | journal = Nature | volume = 408 | issue = 6809 | pages = 211–216 | date = November 2000 | pmid = 11089976 | doi = 10.1038/35041591 | s2cid = 205010648 | bibcode = 2000Natur.408..211K }}
• CXCR4,{{cite journal | vauthors = Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, Bucala R, Weber C, Bernhagen J | title = A functional heteromeric MIF receptor formed by CD74 and CXCR4 | journal = FEBS Letters | volume = 583 | issue = 17 | pages = 2749–2757 | date = September 2009 | pmid = 19665027 | pmc = 2911026 | doi = 10.1016/j.febslet.2009.07.058 | bibcode = 2009FEBSL.583.2749S }}{{cite journal | vauthors = Schrader J, Deuster O, Rinn B, Schulz M, Kautz A, Dodel R, Meyer B, Al-Abed Y, Balakrishnan K, Reese JP, Bacher M | title = Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown | journal = BMC Cancer | volume = 9 | pages = 464 | date = December 2009 | pmid = 20038293 | pmc = 2810303 | doi = 10.1186/1471-2407-9-464 | doi-access = free }}{{cite journal | vauthors = 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 | title = Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus | journal = Journal of Cellular Physiology | volume = 215 | issue = 3 | pages = 665–675 | date = June 2008 | pmid = 18064633 | doi = 10.1002/jcp.21346 | s2cid = 36047003 }} and
• RPS19.{{cite journal | vauthors = 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 | title = Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function | journal = The Journal of Biological Chemistry | volume = 284 | issue = 12 | pages = 7977–7985 | date = March 2009 | pmid = 19155217 | pmc = 2658091 | doi = 10.1074/jbc.M808620200 | doi-access = free }}

MIF is a potential drug target for sepsis, rheumatoid arthritis, and cancer.{{cite journal | vauthors = Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J | title = Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease | journal = Microbes and Infection | volume = 4 | issue = 4 | pages = 449–460 | date = April 2002 | pmid = 11932196 | doi = 10.1016/S1286-4579(02)01560-5 }}{{cite journal | vauthors = Bloom J, Sun S, Al-Abed Y | title = MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development | journal = Expert Opinion on Therapeutic Targets | volume = 20 | issue = 12 | pages = 1463–1475 | date = December 2016 | pmid = 27762152 | doi = 10.1080/14728222.2016.1251582 | s2cid = 36752674 }}

File:Parasite-Produced MIF Cytokine in Immune Evasion, Invasion, and Pathogenesis.jpg

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.{{cite journal | vauthors = Ghosh S, Jiang N, Farr L, Ngobeni R, Moonah S | title = Parasite-Produced MIF Cytokine: Role in Immune Evasion, Invasion, and Pathogenesis | journal = Frontiers in Immunology | volume = 10 | pages = 1995 | date = 21 August 2019 | pmid = 31497025 | pmc = 6712082 | doi = 10.3389/fimmu.2019.01995 | doi-access = free }}{{cite book | vauthors = Bennett JE, Dolin R, Blaser MJ | title = Principles and Practice of Infectious Diseases | pages = 32 | date = 2014 | publisher = Elsevier Health Sciences | isbn = 978-1-4557-4801-3 | url = https://books.google.com/books?id=BseNCgAAQBAJ&pg=PA32 }} A preclinical study showed that blocking parasite MIF improves outcome in severe protozoan infections.{{cite journal | vauthors = Ghosh S, Padalia J, Ngobeni R, Abendroth J, Farr L, Shirley DA, Edwards T, Moonah S | title = Targeting Parasite-Produced Macrophage Migration Inhibitory Factor as an Antivirulence Strategy With Antibiotic-Antibody Combination to Reduce Tissue Damage | journal = The Journal of Infectious Diseases | volume = 221 | issue = 7 | pages = 1185–1193 | date = March 2020 | pmid = 31677380 | pmc = 7325720 | doi = 10.1093/infdis/jiz579 | doi-access = free }} Examples of protozoans with MIF homologs that have been reported:

• Entamoeba histolytica,{{cite journal | vauthors = Ngobeni R, Abhyankar MM, Jiang NM, Farr LA, Samie A, Haque R, Moonah SN | title = Entamoeba histolytica-Encoded Homolog of Macrophage Migration Inhibitory Factor Contributes to Mucosal Inflammation during Amebic Colitis | journal = The Journal of Infectious Diseases | volume = 215 | issue = 8 | pages = 1294–1302 | date = April 2017 | pmid = 28186296 | pmc = 5853319 | doi = 10.1093/infdis/jix076 }}
• Plasmodium falciparum,{{cite journal | vauthors = Sun T, Holowka T, Song Y, Zierow S, Leng L, Chen Y, Xiong H, Griffith J, Nouraie M, Thuma PE, Lolis E, Janse CJ, Gordeuk VR, Augustijn K, Bucala R | title = A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 31 | pages = E2117–E2126 | date = July 2012 | pmid = 22778413 | pmc = 3411961 | doi = 10.1073/pnas.1206573109 | doi-access = free }}
• Toxoplasma gondii,{{cite journal | vauthors = Sommerville C, Richardson JM, Williams RA, Mottram JC, Roberts CW, Alexander J, Henriquez FL | title = Biochemical and immunological characterization of Toxoplasma gondii macrophage migration inhibitory factor | journal = The Journal of Biological Chemistry | volume = 288 | issue = 18 | pages = 12733–12741 | date = May 2013 | pmid = 23443656 | pmc = 3642319 | doi = 10.1074/jbc.M112.419911 | doi-access = free }}
• Leishmania,{{cite journal | vauthors = Holowka T, Castilho TM, Garcia AB, Sun T, McMahon-Pratt D, Bucala R | title = Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence | journal = FASEB Journal| volume = 30 | issue = 6 | pages = 2249–2265 | date = June 2016 | pmid = 26956417 | pmc = 4871794 | doi = 10.1096/fj.201500189R | doi-access = free }}
• Trichomonas vaginalis.{{cite journal | vauthors = Twu O, Dessí D, Vu A, Mercer F, Stevens GC, de Miguel N, Rappelli P, Cocco AR, Clubb RT, Fiori PL, Johnson PJ | title = Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 22 | pages = 8179–8184 | date = June 2014 | pmid = 24843155 | pmc = 4050605 | doi = 10.1073/pnas.1321884111 | bibcode = 2014PNAS..111.8179T | doi-access = free }}

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Category:Immune system