Alternative titles; symbols
HGNC Approved Gene Symbol: MIF
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:23,894,383-23,895,223 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | {Rheumatoid arthritis, systemic juvenile, susceptibility to} | 604302 | 3 |
Migration inhibitory factor for guinea pig macrophages was the first lymphokine to be discovered (Bloom and Bennett, 1966; David, 1966). Expression of MIF activity was found to correlate well with delayed hypersensitivity and cellular immunity in humans. MIF activity could be detected in the synovia of patients with rheumatoid arthritis. The expression of MIF at sites of inflammation suggested a role for the mediator in regulating the function of macrophages in host defense. Weiser et al. (1989) isolated a cDNA encoding human macrophage migration inhibitory factor.
By Northern blot analysis, Paralkar and Wistow (1994) demonstrated a single size of MIF mRNA (about 800 nucleotides) in all human tissues examined. In contrast to previous reports, they found no evidence for multiple genes for MIF in the human genome.
Paralkar and Wistow (1994) showed that the MIF gene is remarkably small; it has 3 exons separated by introns of only 189 and 95 bp, and covers less than 1 kb.
Kozak et al. (1995) found that the exon/intron structure of the mouse Mif gene resembles that of the human gene. Bozza et al. (1995) found that the mouse Mif gene spans less than 0.7 kb of chromosomal DNA and is composed of 3 exons.
Esumi et al. (1998) presented evidence that the gene for D-dopachrome tautomerase (DDT; 602750) in human and mouse is identical in exon structure to MIF. Both genes have 2 introns that are located at equivalent positions, relative to a 2-fold repeat in protein structure. Although in similar positions, the introns are in different phases relative to the open reading frame. Other members of this superfamily exist in nematodes and a plant, and a related gene in C. elegans shares an intron position with MIF and DDT. In addition to similarities in structure, the genes for DDT and MIF are closely linked on human chromosome 22 and mouse chromosome 10.
Bernhagen et al. (1993) identified MIF as a major secreted protein released by anterior pituitary cells in culture and in vivo in response to stimulation with bacterial lipopolysaccharide. They concluded that it plays a central role in the toxic response to endotoxemia and possibly septic shock.
Bucala (1996) reviewed studies that led to the discovery of a pituitary mediator that appeared to act as the counter-regulatory hormone for glucocorticoid action within the immune system. Isolated as a product of murine anterior pituitary cells, this peptide was sequenced and found to be the mouse homolog of MIF. MIF has the unique property of being released from macrophages and T cells in response to physiologic concentrations of glucocorticoids. The secretion of MIF is tightly regulated and decreases at high, antiinflammatory steroid concentrations. Once released, MIF 'overrides' or counter-regulates the immunosuppressive effects of steroids on immune cell activation and cytokine production. Bucala (1996) stated that because glucocorticoids are an integral part of the host's global response to infection or tissue invasion, the physiologic role of MIF is to act at an inflammatory site or lymph node to counterbalance the profound inhibitory effect of steroids on the immune response.
Using full-length MIF as bait in a yeast 2-hybrid screen of a brain cDNA library, Kleemann et al. (2000) captured Jun activation domain-binding protein (JAB1, or COPS5; 604850) as an interacting partner of MIF. By coimmunoprecipitation and pull-down experiments, Kleemann et al. (2000) confirmed the specific MIF-JAB1 association. Confocal microscopic analysis demonstrated that the MIF-JAB1 complex is localized in the cytosol near the peripheral plasma membrane, suggesting a potential connection between MIF and the integrin signaling pathways. Luciferase reporter and gel shift analyses showed that endogenous and exogenous MIF inhibited JAB1-induced activator protein-1 (AP1; 165160) transcriptional activity but did not interfere with nuclear factor kappa-B (NFKB; 164011) activity. Likewise, recombinant MIF inhibited JAB1-stimulated and tumor necrosis factor (TNF; 191160)-induced JNK (601158) activity. MIF also induced p27 (CDKN1B; 600778) expression and mirrored CDKN1B-mediated growth arrest through inhibition of JAB1-dependent degradation of CDKN1B. Mutation analysis indicated that a 16-residue MIF peptide spanning amino acids 50 through 65, including cys60, strongly competed with wildtype MIF for JAB1 binding. Kleemann et al. (2000) suggested that signaling through MIF-JAB1 is independent of a potential MIF receptor and noted that JAB1 is the only protein demonstrated to interact with MIF.
From the parasitic nematode Brugia malayi, an etiologic agent of lymphatic filariasis, Pastrana et al. (1998) cloned a cDNA encoding a protein (BmMif) that is 42% identical to human MIF. MIF homologs were also found in related filarial species. Functional analysis demonstrated that both parasite- and human-derived MIF, when placed with cells, inhibited random migration of monocytes/macrophages, but when placed away from cells increased monocyte/macrophage migration. Pastrana et al. (1998) concluded that filarial parasites produce cytokine homologs that have the potential to modify the host immunologic environment, thus affecting the ability of the parasite to survive in vivo.
Roger et al. (2001) showed that mouse macrophages transfected with antisense Mif mRNA and macrophages from Mif -/- mice are hyporesponsive to lipopolysaccharide (LPS) stimulation, but not stimulation by gram-positive bacteria, as shown by reduced TNFA and IL6 (147620) production. The Mif antisense-treated cells and macrophages from Mif-deficient mice, expressed reduced Tlr4 (603030), but not Tlr2 (603028), mRNA and protein. EMSA and promoter analysis indicated that deficient Mif expression impairs basal PU.1 (165170) transcription factor activity of the mouse Tlr4 gene, resulting in reduced Tlr4 protein expression and responsiveness to LPS and gram-negative bacteria. Roger et al. (2001) suggested that inhibition of MIF activity may benefit people with gram-negative septic shock.
Amin et al. (2003) determined that MAPK (see MAPK1; 176948) and PI3K (see PIK3CA; 171834) were critical for MMIF-dependent migration of human dermal microvascular endothelial cells through basement membrane, but Src (190090) and p38 kinase (600289) were nonessential. Recombinant MMIF also induced time-dependent increases in phosphorylation of proteins along the MAPK and PI3K signaling pathways.
Using immunofluorescence microscopy, Bernhagen et al. (2007) showed that cells expressing MIF induced monocyte arrest through CXCR2 (IL8RB; 146928) and T-cell arrest through CXCR4 (162643), but not through CXCR1 (IL8RA; 146929) or CXCR3 (300574). Transwell analysis revealed that MIF stimulated leukocyte chemotaxis through CXCR2 and CXCR4 and elicited rapid integrin (e.g., ITGAL (153370)/ITGB2 (600065)) activation, as well as calcium mobilization. Flow cytometry, fluorescence microscopy, and pull-down analyses showed that MIF interacted with CXCR2 and CXCR4 and colocalized with CD74 (142790). Monocyte arrest in atherosclerosis-prone mice required Mif and Cxcr2, and inflammatory responses induced by Mif in mice also relied on Cxcr2. Antibody-mediated blockade of Mif, but not of the canonical ligands of Cxcr2 and Cxcr4, in Apoe (107741) -/- mice on a high-fat diet with atherosclerosis led to plaque regression. Bernhagen et al. (2007) proposed that targeting MIF in atherosclerotic individuals may be a therapeutic option.
Arjona et al. (2007) showed that patients with acute West Nile virus (WNV; see 610379) infection had increased levels of MIF in plasma and cerebrospinal fluid. Studies in mice (see ANIMAL MODEL) showed that MIF is involved in WNV pathogenesis and suggested that pharmacotherapeutic approaches targeting MIF may be useful in treating WNV encephalitis.
Miller et al. (2008) showed that MIF, an upstream regulator of inflammation, is released in the ischemic heart, where it stimulates AMPK (see 602739) activation through CD74, promotes glucose uptake, and protects the heart during ischemia-reperfusion injury. Germline deletion of the Mif gene impairs ischemic AMPK signaling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischemia, functionally linking inflammation and metabolism in the heart. Miller et al. (2008) anticipated that genetic variation in MIF expression may influence the response of the human heart to ischemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.
By interspecific backcross analyses, Kozak et al. (1995) showed that the mouse Mif gene maps to chromosome 10. They mapped 9 additional loci containing related sequences, apparently all processed pseudogenes, to mouse chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. Bozza et al. (1995) likewise mapped the gene to mouse chromosome 10 (between Bcr and S100b, which had been mapped to human chromosomes 22q11 and 21q22.3, respectively). They analyzed several pseudogenes and mapped 3 of them to mouse chromosomes 1, 9, and 17.
Kozak et al. (1995) determined that the human genome contains no MIF pseudogenes. Budarf et al. (1997) performed somatic cell hybrid panel PCR with human-specific primers to localize the gene to human chromosome 22q11.2. They also performed fluorescence in situ hybridization and found unequivocal mapping of MIF to chromosome 22q. Kozak et al. (1995) had mapped the human MIF gene to chromosome 19.
Donn et al. (2001) identified a G-to-C transition at position -173 of the MIF gene (153620.0001) and screened for this polymorphism in 117 patients with systemic juvenile rheumatoid arthritis (604302) and 172 unrelated healthy controls. They found that individuals possessing the MIF-173C allele had an increased risk of the disease (p = 0.0005). Donn et al. (2002) screened for the MIF-173C allele in a group of 88 patients with juvenile rheumatoid arthritis of varying clinical phenotypes. They confirmed the increased risk of susceptibility to juvenile rheumatoid arthritis and also found that the increased risk was not limited to any one clinical subgroup.
Among its many biologic functions, MIF induces inflammation at the interface between the immune system and the hypothalamus-pituitary-adrenal stress axis. Koebernick et al. (2002) showed that Mif-deficient knockout mice failed to control an infection with wildtype Salmonella typhimurium. Various measures indicated that MIF is a key mediator in the host response to this infection. MIF not only promotes development of a protective Th1 response but ameliorates disease by altering levels of reactive nitrogen intermediates and corticosteroid hormones, which both exert immunosuppressive functions.
Wang et al. (2006) noted that increased levels of MIF, possibly derived from eosinophils, has been observed in bronchoalveolar lavage fluid (BALF) of asthmatic patients (Rossi et al., 1998). Wang et al. (2006) compared Mif -/- mice with wildtype mice using a mouse model of pulmonary inflammation. Mif -/- mice had significant reductions in serum IgE and alveolar inflammatory cell recruitment, reduced serum and BALF cytokines and chemokines, and impaired Cd4 (186940) T-cell activation. Wildtype mice displayed increased Mif levels in BALF. The antigen-induced airway inflammation phenotype could be restored in Mif -/- mice by reconstitution with wildtype mast cells. Wang et al. (2006) concluded that mast cell-derived MIF is essential for experimentally induced airway allergic disease.
Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to WNV lethality. PCR and confocal microscopy showed that mice lacking Mif had lower viral load and brain inflammation, as well as lower circulating Tnf, than wildtype mice. Injection of Evans blue dye demonstrated that the blood-brain barrier remained intact in Mif -/- mice, but not in wildtype mice, after WNV challenge. Arjona et al. (2007) concluded that MIF is involved in WNV pathogenesis and that pharmacotherapeutic approaches targeting MIF may be useful in treating WNV encephalitis.
The symbol MIF is also used for mullerian inhibitory factor (600957), but to avoid confusion, AMH, for anti-mullerian hormone, has been declared the preferred symbol for the latter gene.
Donn et al. (2001) identified a G-to-C transition at position -173 of the MIF gene and screened for this polymorphism in 117 patients with systemic juvenile rheumatoid arthritis (604302) and 172 unrelated healthy controls. They found that individuals possessing the MIF-173C allele had an increased risk of the disease (p = 0.0005).
De Benedetti et al. (2003) studied 136 patients with systemic juvenile rheumatoid arthritis and found that the MIF-173C allele was associated with higher serum and synovial fluid levels of MIF, poorer response to glucocorticoid treatment, persistence of active disease, and a poor functional outcome.
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Bernhagen, J., Calandra, T., Mitchell, R. A., Martin, S. B., Tracey, K. J., Voelter, W., Manogue, K. R., Cerami, A., Bucala, R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365: 756-759, 1993. Note: Erratum: Nature 378: 419 only, 1995. [PubMed: 8413654] [Full Text: https://doi.org/10.1038/365756a0]
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Donn, R. P., Shelley, E., Ollier, W. E. R., Thomson, W., the British Paediatric Rheumatology Study Group. A novel 5-prime-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44: 1782-1785, 2001. [PubMed: 11508429] [Full Text: https://doi.org/10.1002/1529-0131(200108)44:8<1782::AID-ART314>3.0.CO;2-#]
Esumi, N., Budarf, M., Ciccarelli, L., Sellinger, B., Kozak, C. A., Wistow, G. Conserved gene structure and genomic linkage for D-dopachrome tautomerase (DDT) and MIF. Mammalian Genome 9: 753-757, 1998. [PubMed: 9716662] [Full Text: https://doi.org/10.1007/s003359900858]
Kleemann, R., Hausser, A., Geiger, G., Mischke, R., Burger-Kentischer, A., Flieger, O., Johannes, F.-J., Roger, T., Calandra, T., Kapurniotu, A., Grell, M., Finkelmeier, D., Brunner, H., Bernhagen, J. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408: 211-216, 2000. [PubMed: 11089976] [Full Text: https://doi.org/10.1038/35041591]
Koebernick, H., Grode, L., David, J. R., Rohde, W., Rolph, M. S., Mittrucker, H.-W., Kaufmann, S. H. E. Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium. Proc. Nat. Acad. Sci. 99: 13681-13686, 2002. [PubMed: 12271144] [Full Text: https://doi.org/10.1073/pnas.212488699]
Kozak, C. A., Adamson, M. C., Buckler, C. E., 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: 405-411, 1995. [PubMed: 7558020] [Full Text: https://doi.org/10.1006/geno.1995.1070]
Miller, E. J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., Young, L. H. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451: 578-582, 2008. [PubMed: 18235500] [Full Text: https://doi.org/10.1038/nature06504]
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Pastrana, D. V., Raghavan, N., Fitzgerald, P., Eisinger, S. W., Metz, C., Bucala, R., Schleimer, R. P., Bickel, C., Scott, A. L. Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect. Immun. 66: 5955-5963, 1998. [PubMed: 9826378] [Full Text: https://doi.org/10.1128/IAI.66.12.5955-5963.1998]
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Rossi, A. G., Haslett, C., Hirani, N., Greening, A. P., Rahman, I., Metz, C. N., Bucala, R., Donnelly, S. C. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF): potential role in asthma. J. Clin. Invest. 101: 2869-2874, 1998. [PubMed: 9637721] [Full Text: https://doi.org/10.1172/JCI1524]
Wang, B., Huang, X., Wolters, P. J., Sun, J., Kitamoto, S., Yang, M., Riese, R., Leng, L., Chapman, H. A., Finn, P. W., David, J. R., Bucala, R., Shi, G.-P. Cutting edge: deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses. J. Immun. 177: 5779-5784, 2006. [PubMed: 17056501] [Full Text: https://doi.org/10.4049/jimmunol.177.9.5779]
Weiser, W. Y., Temple, P. A., Witek-Giannotti, J. S., Remold, H. G., Clark, S. C., David, J. R. Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc. Nat. Acad. Sci. 86: 7522-7526, 1989. [PubMed: 2552447] [Full Text: https://doi.org/10.1073/pnas.86.19.7522]