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 MIFgene. MIF is an important regulator of innate immunity.
Bacterial antigens stimulate white blood cells to release MIF into the blood stream. 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.
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.
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). MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfidereductase.
^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". Genomics27 (3): 405–11. doi:10.1006/geno.1995.1070. PMID7558020.
^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. PMID14502271.
^Barret, James (1980). Basic Immunology and its Medical Application (2 ed.). St.Louis: The C.V. Mosby Company. ISBN0-8016-0495-8.
^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. PMID20829186.
^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. PMID16115028.
^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. PMID16474429.
^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. PMID12681488.
^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. PMID20034881.
^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". Pain148 (2): 275–83. doi:10.1016/j.pain.2009.11.011. PMID20005040.
^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". Nature408 (6809): 211–6. doi:10.1038/35041591. PMID11089976.
^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. PMID11932196.
^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 Neurosciences253: 265. doi:10.1007/s00406-003-0451-4.
^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 Psychiatry5: e601. doi:10.1038/tp.2015.91.
^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". Shock24 (6): 556–63. doi:10.1097/01.shk.0000183238.70374.a8. PMID16317387.