Abstract
The macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and regulates the anti-inflammator effects of glucocorticoids. An important role for MIF within the cytokine cascade is to act in concert with endogenous glucocorticoids to control the set-point and magnitude of the inflammatory response. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis. MIF also has been linked to the development of joint damage and disease pathology in experimental animal models. We describe herein a novel CATT-tetranucleotide repeat polymorphism at position −794 of the human Mif gene and show that it functionally affects the activity of the MIF promoter in gene reporter assays. We describe four genotypes which comprise 5, 6, 7, or 8-CATT repeat units and show that the 5-CATT allele has the lowest level of basal and stimulated MIF promoter activity in vitro. The presence of the low expressing, 5-CATT repeat allele correlated with low disease severity in a cohort of rheumatoid arthritis patients.
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References
Bucala R . MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response FASEB J 1996 10: 1607–1613
Leech M, Metz C, Hall P et al. Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids Arthritis Rheum 1999 42: 1601–1608
Bernhagen J, Calandra T, Mitchell RA et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxemia Nature 1993 365: 756–759
Bernhagen J, Calandra T, Bucala R . The emerging role of MIF in septic shock and infection Biotherapy 1995 8: 123–127
Donnelly SC, Bucala R, Metz CN et al. Macrophage migration inhibitory factor and acute lung injury Chest 1999 116: 111S
Yang NS, NikolicPaterson DJ, Ng YY et al. Reversal of established rat crescentic glomerulonephritis by blockade of macrophage migration inhibitory factor (MIF): potential role of MIF in regulating glucocorticoid production Mol Med 1998 4: 413–424
David JR . Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction Proc Natl Acad Sci USA 1996 56: 72–77
Calandra T, Bernhagen J, Mitchell RA, Bucala R . Macrophage is an important and previously unrecognized source of macrophage-migration inhibitory factor J Exp Med 1994 179: 1895–1902
Onodera S, Tanji H, Suzuki K et al. High expression of macrophage migration inhibitory factor in the synovial tissue of rheumatoid joints Cytokine 1999 11: 163–167
Calandra T, Echtenacher B, Roy DL et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor Nat Med 2000 6: 164–170
Bacher M, Metz CN, Calandra T et al. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation Proc Natl Acad Sci USA 1996 93: 7849–7854
Satoskar AR, Bozza M, Rodriguez SM, Lin G, David JR . Migration-inhibitory factor gene-deficient mice are susceptible to cutaneous Leishmania major infection Infect Immun 2001 69: 906–911
Benigni F, Atsumi T, Calandra T et al. The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle J Clin Invest 2000 106: 1291–1300
Abe R, Peng T, Sailors J, Bucala R, Metz CN . Regulation of the CTL response by macrophage migration inhibitory factor J Immunol 2001 166: 747–753
Bernhagen J, Calandra T, Mitchell RA et al. Purification and characterization of the cytokine macrophage- migration inhibitory factor (MIF) FASEB J 1994 8: A1417
Onodera S, Kaneda K, Mizue Y et al. Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis J Biol Chem 2000 275: 444–450
Meyer-Siegler K . Macrophage migration inhibitory factor increases MMP-2 activity in DU-145 prostate cells Cytokine 2000 12: 914–921
Mitchell RA, Metz CN, Peng T, Bucala R . Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action J Biol Chem 1999 274: 18100–18106
Hudson JD, Shoaibi MA, Maestro R et al. A proinflammatory cytokine inhibits p53 tumor suppressor activity J Exp Med 1999 190: 1375–1382
Mitchell RA, Liao H, Chesney J et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response Proc Natl Acad Sci USA 2002 99: 345–350
Alam J, Cook JL . Reporter genes: application to the study of mammalian gene transcription Anal Biochem 1990 188: 245–254
Naylor LH . Reporter gene technology: the future looks bright Biochem Pharmacol 1999 58: 749–757
Seamon KB, Daly JW . Forskolin: a unique diterpene activator of cyclic AMP-generating systems J Cyclic Nucleotide Res 1981 7: 201–224
McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria Nature 1994 371: 508–510
Francis SE, Camp NJ, Dewberry RM et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease Circulation 1999 99: 861–866
Buchs N, di Giovine FS, Silvestri T et al. IL-1B and IL-1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels Genes Immun 2001 2: 222–228
Mu H, Chen JJ, Jiang Y et al. Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope Arthritis Rheum 1999 42: 438–442
van Krugten MV, Huizinga TW, Kaijzel EL et al. Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis Genes Immun 1999 1: 91–96
Sampey AV, Hall PH, Mitchell RA, Metz CN, Morand EF . Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor Arthritis Rheum 2001 44: 1273–1280
Mikulowska A, Metz CN, Bucala R, Holmdahl R . Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice J Immunol 1997 158: 5514–5517
Leech M, Metz C, Bucala R, Morand EF . Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis Arthritis Rheum 2000 43: 827–833
Nimer S, Fraser J, Richards J, Lynch M, Gasson J . The repeated sequence CATT(A/T) is required for granulocyte-macrophage colony-stimulating factor promoter activity Mol Cell Biol 1990 10: 6084–6088
Nimer SD, Zhang W, Kwan K et al. Adjacent, cooperative elements form a strong, constitutive enhancer in the human granulocyte-macrophage colony-stimulating factor gene Blood 1996 87: 3694–3703
Ye J, Young HA, Ortaldo JR, Ghosh P . Identification of a DNA binding site for the nuclear factor YY1 in the human GM-CSF core promoter Nucleic Acids Res 1994 22: 5672–5678
Ye J, Zhang X, Dong Z . Characterization of the human granulocyte-macrophage colony-stimulating factor gene promoter: an AP1 complex and an Sp1-related complex transactivate the promoter activity that is suppressed by a YY1 complex Mol Cell Biol 1996 16: 157–167
Cohen LE, Wondisford FE, Radovick S . Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin Endocrinol Metab Clin North Am 1996 25: 523–540
Calandra T, Bernhagen J, Metz CN et al. MIF as a glucocorticoid-induced modulator of cytokine production Nature 1995 377: 68–71
Nishino T, Bernhagen J, Shiiki H, Calandra T, Dohi K, Bucala R . Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland Mol Med 1995 1: 781–788
Baerwald CG, Mok CC, Tickly M et al. Corticotropin releasing hormone (CRH) promoter polymorphisms in various ethnic groups of patients with rheumatoid arthritis Z Rheumatol 2000 59: 29–34
Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS . Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis Arthritis Rheum 1992 35: 1281–1288
Donn RP, Shelley E, Ollier WE, Thomson W . A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis Arthritis Rheum 2001 44: 1782–1785
Feldmann M, Maini RN . Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 1901 19: 163–196
Calandra T, Bernhagen J, Mitchell RA, Cerami A, Bucala R . MIF, a previously unrecognized macrophage cytokine, induces macrophages to secrete TNF-alpha and overcomes dexamethasone-suppression of TNF secretion Clin Res 1994 42: A138
Paralkar V, Wistow G . Cloning the human gene for macrophage migration inhibitory factor (MIF) Genomics 1994 19: 48–51
Tsuda T, Nakagawa G, Sato M, Yagi K . Separation of nucleotides by high-voltage capillary electrophoresis J Appl Biochem 1983 5: 330–336
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The authors would like to acknowledge support form the NIH (RB – 1R01-AI35931, 1R01-AI42310; PKG – RO1-AR44222), The Wellcome Trust, and The Picower Institute for Medical Research. We also thank Ms Nina Kohn for expert assistance with biostatistical analysis.
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Baugh, J., Chitnis, S., Donnelly, S. et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3, 170–176 (2002). https://doi.org/10.1038/sj.gene.6363867
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DOI: https://doi.org/10.1038/sj.gene.6363867
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