Macrophage Migration Inhibitory Factor (MIF): A Pro-Inflammatory Mediator of Sepsis

  • Christian Martin
  • Thierry Roger
  • Thierry Calandra
Part of the Perspectives on Critical Care Infectious Diseases book series (CCID, volume 2)


Over the last ten years, the protein known as macrophage migration inhibitory factor (MIF) has emerged to be a central cytokine of the innate immune system and was found to play an important part in the control of inflammatory responses. MIF is considered to be one of the first cytokine activities described. Investigations of the mechanisms of delayed-type hypersensitivity reactions conducted in the late 1960s have led to the recognition of an activity that inhibited the random migration of guinea pig peritoneal exudate cells. In 1966, Bloom and David associated this macrophage migration inhibitory activity to a soluble, non-dialyzable factor released by sensitized lymphocytes (1,2). These reports stimulated the curiosity of immunologists as MIF was one of the first lymphokines to be described. Over the next 20 years, MIF was found to enhance a broad-spectrum of macrophage functions, including adherence, phagocytosis, spreading, and tumoricidal activity (reviewed in reference 3). The biological activities ascribed to MIF remained uncertain as cytokines such IFNγ and IL-4 also were observed to inhibit macrophage migration. The cloning of a human MIF cDNA in 1989 was a milestone in the investigations of the biochemical and biological properties of MIF (4). However, initial studies were performed with unpurified recombinant MIF protein that was later found to contain a mitogenic contaminant.


Septic Shock Migration Inhibitory Factor Macrophage Migration Inhibitory Factor Migration Inhibitory Factor Expression Migration Inhibitory Factor Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 1966; 153:80–82.PubMedCrossRefGoogle Scholar
  2. 2.
    David J. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. PNAS 1966;56:72–77.PubMedCrossRefGoogle Scholar
  3. 3.
    Calandra T, Bucala R. Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system. Critical Reviews in Immunology 1997;17:77–88.PubMedCrossRefGoogle Scholar
  4. 4.
    Weiser WY, Temple PA, Witek-Gianotti JS, Remold HG, Clark SC, David JR. Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. PNAS 1989;86:7522–7526.PubMedCrossRefGoogle Scholar
  5. 5.
    Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993;365:756–759.PubMedCrossRefGoogle Scholar
  6. 6.
    Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 1994;179:1895–1902.PubMedCrossRefGoogle Scholar
  7. 7.
    Bacher M, Meinhardt A, Lan HY, Metz CN, Chesney JA, Calandra T, Gemsa D, Donnelly T, Atkins RC, Bucala R. MIF expression in experimentally-induced endotoxemia. Am J Pathol 1997;150(1):235–246.PubMedGoogle Scholar
  8. 8.
    Bernhagen J, Calandra T, Bucala R. Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features. J Mol Med 1998;76:151–161.PubMedCrossRefGoogle Scholar
  9. 9.
    Swope MD, Lolis E. Macrophage migration inhibitory factor: cytokine, hormone, or enzyme? Rev Physiol Biochem Pharmacol 1999;139:1–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Paralkar V, Wistow G. Cloning the human gene for macrophage migration inhibitory factor (MIF). Genomics 1994; 19: 48–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Mitchell R, Bacher M, Bernhagen J, Pushkarskaya T, Seldin M, Bucala R. Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF). J Immunol 1995;154:3863–3870.PubMedGoogle Scholar
  12. 12.
    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 1995;27:405–411.PubMedCrossRefGoogle Scholar
  13. 13.
    Bozza M, Kolakowski LF, Jenkins NA, Gilbert DJ, Copeland NG, David JR, Gerard C. Structural characterization and chromosomal location of the mouse macrophage migration inhibitory factor gene and pseudogenes. Genomics 1996;27:412–419.CrossRefGoogle Scholar
  14. 14.
    Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, Gerard C, David JR. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 1999;189(2):341–346.PubMedCrossRefGoogle Scholar
  15. 15.
    Budarf M, McDonald T, Sellinger B, Kozak C, Graham C, Wistow G. Localization of the human gene for macrophage migration inhibitory factor (MIF) to chromosome 22q11.2. Genomics 1997;39(2):235–236.PubMedCrossRefGoogle Scholar
  16. 16.
    Wistow GJ, Shaughnessy MP, Lee DC, Hodin J, Zelenka PS. A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens. PNAS 1993;90:1272–1275.PubMedCrossRefGoogle Scholar
  17. 17.
    Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, Bucala R. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry 1994;33:14144–14155.PubMedCrossRefGoogle Scholar
  18. 18.
    Esumi N, Budarf M, Ciccarelli L, Sellinger B, Kozak CA, Wistow G. Conserved gene structure and genomic linkage for D-dopachrome tautomerase (DDT) and MIF. Mamm Genome 1998;9(9):753–757.PubMedCrossRefGoogle Scholar
  19. 19.
    Waeber G, Thompson N, Chautard T, Steinmann M, Nicod P, Pralong FP, Calandra T, Gaillard RC. Transcriptional activation of the macrophage migration-inhibitory factor gene by the corticotropin-releasing factor is mediated by the cyclic adenosine 3′,5′-monophosphate responsive element-binding protein CREB in pituitary cells. Mol Endocrinol 1998;12(5):698–705.PubMedCrossRefGoogle Scholar
  20. 20.
    Ishizaka K, Ishii Y, Nakano T, Sugie K. Biochemical basis of antigen-specific suppressor T cell factors: controversies and possible answers. Adv Immunol 2000;74:1–60.PubMedCrossRefGoogle Scholar
  21. 21.
    Sugimoto H, Taniguchi M, Nakagawa A, Tanaka I, Suzuki M, Nishihira J. Crystal structure of human D-dopachrome tautomerase, a homologue of macrophage migration inhibitory factor, at 1.54 A resolution. Biochemistry 1999;38(11):3268–3279.PubMedCrossRefGoogle Scholar
  22. 22.
    Sun HW, Swope M, Cinquina C, Bedarkar S, Bernhagen J, Bucala R, Lolis E. The subunit structure of human macrophage migration inhibitory factor: evidence for a trimer. Protein Engineering 1996;9(8):631–635.PubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki M, Sugimoto H, Nakagawa A, Tanaka I, Nishihira J, Sakai M. Crystal structure of the macrophage migration inhibitory factor from rat liver. Nature Structural Biology 1996;3:259–266.PubMedCrossRefGoogle Scholar
  24. 24.
    Subramanya HS, Roper DI, Dauter Z, Dodson EJ, Davies GJ, Wilson KS, Wigley DB. Enzymatic ketonization of 2-hydroxymuconate: specificity and mechanism investigated by the crystal structures of two isomerases. Biochemistry 1996;95(3):792–802.CrossRefGoogle Scholar
  25. 25.
    Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H. The immunoregulatory mediator macrophage migration inhibitory factor (MIF) calalyzes a tautomerization reaction. Molecular Medicine 1996;2(1):143–149.PubMedGoogle Scholar
  26. 26.
    Rosengren E, Aman P, Thelin S, Hansson C, Ahlfors S, Björk P, Jacobsson L, Rorsman H. The macrophage migration inhibitory factor MIF is a phenylpyruvate tautomerase. FEBS Letters 1997;417:85–88.PubMedCrossRefGoogle Scholar
  27. 27.
    Bendrat K, Al-Abed Y, Callaway DJE, Peng T, Calandra T, Metz CN, Bucala R. Biochemical and mutational investigations of the enzymatic activity of macrophage migration inhibitory factor. Biochemistry 1997;36(49):15356–15362.PubMedCrossRefGoogle Scholar
  28. 28.
    Hermanowski-Vosatka A, Mundt SS, Ayala JM, Goyal S, Hanlon WA, Czerwinski RM, Wright SD, Whitman CP. Enzymatically inactive macrophage migration inhibitory factor inhibits monocyte chemotaxis and random migration. Biochemistry 1999;38(39):12841–12849.PubMedCrossRefGoogle Scholar
  29. 29.
    Kleemann R, Kapurniotu A, Frank RW, Gessner A, Mischke R, Flieger O, Juttner S, Brunner H, Bernhagen J. Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 1998;280(1):85–102.PubMedCrossRefGoogle Scholar
  30. 30.
    Calandra T, Spiegel LA, Metz CN, Bucala R. Macrophage migration inhibitory factor (MIF) is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. PNAS 1998;95:11383–11388.PubMedCrossRefGoogle Scholar
  31. 31.
    Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, Heumann D, Mannel D, Bucala R, Glauser MP. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000;6(2):164–170.PubMedCrossRefGoogle Scholar
  32. 32.
    Martiney JA, Sherry B, Metz CN, Espinoza M, Ferrer AS, Calandra T, Broxmeyer HE, Bucala R. Macrophage migration inhibitory factor release by macrophages after ingestion of plasmodium chabaudi-infected erythrocytes: possible role in the pathogenesis of malarial anemia. Infect Immun 2000;68(4):2259–2267.PubMedCrossRefGoogle Scholar
  33. 33.
    Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995;377:68–71.PubMedCrossRefGoogle Scholar
  34. 34.
    Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. PNAS 1996;93:7849–7854.PubMedCrossRefGoogle Scholar
  35. 35.
    Wymann D, Bluggel M, Kalbacher H, Blesken T, Akdis CA, Meyer HE, Blaser K. Human B cells secrete migration inhibition factor (MIF) and present a naturally processed MIF peptide on HLA-DRB1*0405 by a FXXL motif. Immunology 1999;96(1):1–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Takahashi A, Iwabuchi K, Suzuki M, Ogasawara K, Nishihira J, Onoé K. Antisense macrophage migration inhibitory factor (MIF) prevents anti-IgM mediated growth arrest and apoptosis of a murine B cell line by regulating cell cycle progression. Microbiol Immunol 1999;43(1):61–67.PubMedGoogle Scholar
  37. 37.
    Swope M, Sun H-W, Blake PR, Lolis E. Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. EMBO Journal 1998;17(13):3534–3541.PubMedCrossRefGoogle Scholar
  38. 38.
    Makita H, Nishimura M, Miyamoto K, Nakano T, Tanino Y, Hirokawa J, Nishihira J, Kawakami Y. Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit CareMed 1998;158:573–579.Google Scholar
  39. 39.
    Rossi AG, Haslett C, Hirani N, Greening AP, Rahman I, Metz CN, Bucala R, Donnelly SC. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest 1999;101(12):2869–2874.CrossRefGoogle Scholar
  40. 40.
    Chen H, Centola M, Altschul SF, Metzger H. Characterization of gene expression in resting and activated mast cells. J Exp:Med 1998;188(9):1657–1668.PubMedCrossRefGoogle Scholar
  41. 41.
    Apte RS, Sinha D, Mayhew E, Wistow GJ, Niederkorn JY. Role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege. J Immunol 1998;160(12):5693–5696.PubMedGoogle Scholar
  42. 42.
    Matsuda A, Tagawa Y, Matsuda H, Nishihira J. Identification and immunohistochemical localization of macrophage migration inhibitory factor in human cornea. FEBS Letters 1996;385:225–228.PubMedCrossRefGoogle Scholar
  43. 43.
    Mitchell RA, Metz CN, Peng T, Bucala R. Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phopholipase A2 activation by macrophage migration inhibitory factor (MIF). J Biol Chem 1999;274(25):18100–18106.PubMedCrossRefGoogle Scholar
  44. 44.
    Jüttner S, Bernhagen J, Metz CN, Röllinghoff M, Bucala R, Gessner A. Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-α. J Immunol 1998;161:2383–2390.PubMedGoogle Scholar
  45. 45.
    Xu D, McSorley SJ, Tetley L, Chatfield S, Dougan G, Chan WL, Satoskar A, David JR, Liew FY. Protective effect on Leishmania major infection of migration inhibitory factor, TNF-alpha, and IFN-gamma administered orally via attenuated Salmonella typhimurium. J Immunol 1998;160(3):1285–1289.PubMedGoogle Scholar
  46. 46.
    Donnelly SC, Haslett C, Reid PT, Grant IS, Wallace WAH, Metz CN, Bruce LJ, Bucala R. Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 1997;3(3):320–323.PubMedCrossRefGoogle Scholar
  47. 47.
    Onodera S, Tanji H, Suzuki K, Kaneda K, Mizue Y, Sagawa A, Nishihira J. High expression of macrophage migration inhibitory factor in the synovial tissues of rheumatoid joints. Cytokine 1999;11(2):163–167.PubMedCrossRefGoogle Scholar
  48. 48.
    Leech M, Metz C, Hall P, Hutchinson P, Gianis K, Smith M, Weedon H, Holdsworth SR, Bucala R, Morand EF. Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of pro inflammatory function and regulation by glucocorticoids. Arthritis Rheum 1999;42(8):1601–1608.PubMedCrossRefGoogle Scholar
  49. 49.
    Metz CN, Bucala R. Role of macrophage migration inhibitory factor in the regulation of the immune response. Adv Immunol 1997;66:197–223.PubMedCrossRefGoogle Scholar
  50. 50.
    Shimizu T, Abe R, Ohkawara A, Mizue Y, Nishihira J. Macrophage migration inhibitory factor is an essential immunoregulatory cytokine in atopic dermatitis. Biochem Biophys Res Commun 1997;240(1):173–178.PubMedCrossRefGoogle Scholar
  51. 51.
    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(7):781–788.PubMedGoogle Scholar
  52. 52.
    Bernhagen J, Bacher M, Calandra T, Metz CN, Doty SB, Donnelly T, Bucala R. An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction. J Exp Med 1996;183:277–282.PubMedCrossRefGoogle Scholar
  53. 53.
    Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kB activity trough induction of IkB synthesis. Science 1995;270:286–290.PubMedCrossRefGoogle Scholar
  54. 54.
    Scheinman RI, Cogswell PC, Lofquist AK, Baldwin Jr AS. Role of transcriptional activation of IkBa mediation of immunosuppression by glucocorticoids. Science 1995;270:283–286.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Christian Martin
    • 1
  • Thierry Roger
    • 1
  • Thierry Calandra
    • 1
  1. 1.Division of Infectious Diseases, Department of Internal MedicineCentre Hospitalier Universitaire VaudoisLausanneSwitzerland

Personalised recommendations