Journal of Molecular Medicine

, Volume 86, Issue 7, pp 761–770 | Cite as

Chemokine-like functions of MIF in atherosclerosis

  • Andreas Schober
  • Jürgen Bernhagen
  • Christian WeberEmail author


The cytokine macrophage migration inhibitory factor (MIF) is a unique pro-inflammatory regulator of many acute and chronic inflammatory diseases. In the pathogenesis of atherosclerosis, chronic inflammation of the arterial wall characterized by chemokine-mediated influx of leukocytes plays a central role. The contribution of MIF to atherosclerotic vascular disease has come into focus of many studies in recent years. MIF is highly expressed in macrophages and endothelial cells of different types of atherosclerotic plaques, and functional studies established the contribution of MIF to lesion progression and plaque inflammation. This proatherogenic effect may partly be explained by the finding that MIF regulates inflammatory cell recruitment to lesion areas. Similar to chemokines, MIF induces integrin-dependent arrest and transmigration of monocytes and T cells. These chemokine-like functions are mediated through interaction of MIF with the chemokine receptors CXCR2 and CXCR4 as a non-canonical ligand. In atherogenic monocyte recruitment, MIF-induced monocyte adhesion involves CD74 and CXCR2, which form a signaling receptor complex. In addition to lesion progression, MIF has been implicated in plaque destabilization, since MIF is predominantly expressed in vulnerable plaques and can induce collagen-degrading matrix metalloproteinases. The latter could be a relevant mechanism in atherosclerotic abdominal aneurysm formation, where MIF expression is correlated with aneurysmal expansion. In summary, MIF has been identified as an important regulator of atherosclerotic vascular disease with exceptional chemokine-like functions. Detailed analysis of the interaction of MIF with its receptors could provide valuable information for drug development for the anti-inflammatory treatment of established and unstable atherosclerosis.


Atherosclerosis Cytokine Chemokine receptor Inflammation Chemokine 

Abbreviations and glossary


macrophage migration inhibitory factor


receptor for chemokines with an CXC motif (CXCL1, -2, -3, -8)


receptor for the CXC chemokine CXCL12


Invariant γ-chain of class II histocompatibility antigens


chemokine ligand with a CXC motif; alternative titles: growth-regulated oncogene protein (GRO)-α, keratinocyte-derived chemokines (KC, mouse homolog)


chemokine ligand with a CXC motif; alternative title: interleukin-8


chemokine ligand with a CC motif; alternative title: Regulated upon activation, normally T-expressed, and secreted (RANTES)


jun-c activation domain-binding protein; binds intracellular MIF


activator protein-1; transcription factor involved in cellular proliferation, transformation and death


platelet-derived growth factor; affects migration and differentiation of smooth muscle cells


Low-density-Lipoprotein receptor deficient mice; develop hyperlipidemia and atherosclerosis on cholesterol-rich diet


Apolipoprotein E-deficient mice; develop hyperlipidemia and atherosclerosis on cholesterol-rich diet


Phosphorylated c-jun transcription factor which activates AP-1 expression


CCAAT/Enhancer-binding protein-β; transcription factor which determines expression of many Interleukin 6-dependent genes

αLβ2- integrin

Heterodimeric leukocyte cell adhesion molecule with a β2- und αL subunit also referred to as leukocyte functional antigen (LFA)-1 or CD18/CD11c


Heterodimeric leukocyte cell adhesion molecule with a β1- und α4 subunit also referred to as very late activation protein (VLA)-4 or CD29/CD49d


Chemokine ligand with a CXC motif, also known as stromal cell-derived factor (SDF)-1


receptor for chemokines with a CXC motif (e.g. CXCL6, -8)


receptor for chemokines with a CXC motif (e.g. CXCL9, -10, -11)


monocytic cell line derived from a patient with acute monocytic leukemia

MMP-1, -2, -9

matrix metalloproteinases; Zn2+-binding endopeptidases that degrade various components of the extracellular matrix


  1. 1.
    Mackay J, Mensah G (2004) The Atlas of heart disease and stroke. World Health Organization, GenevaGoogle Scholar
  2. 2.
    Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809PubMedCrossRefGoogle Scholar
  3. 3.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874PubMedCrossRefGoogle Scholar
  4. 4.
    Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695PubMedCrossRefGoogle Scholar
  5. 5.
    Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86:515–581PubMedCrossRefGoogle Scholar
  6. 6.
    Weber C, Schober A, Zernecke A (2004) Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol 24:1997–2008PubMedCrossRefGoogle Scholar
  7. 7.
    Weber C (2003) Novel mechanistic concepts for the control of leukocyte transmigration: specialization of integrins, chemokines, and junctional molecules. J Mol Med 81:4–19PubMedGoogle Scholar
  8. 8.
    Laudanna C, Alon R (2006) Right on the spot. Chemokine triggering of integrin-mediated arrest of rolling leukocytes. Thromb Haemost 95:5–11PubMedGoogle Scholar
  9. 9.
    Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:756–759PubMedCrossRefGoogle Scholar
  10. 10.
    Bernhagen J, Bacher M, Calandra T, Metz CN, Doty SB, Donnelly T, Bucala R (1996) An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction. J Exp Med 183:277–282PubMedCrossRefGoogle Scholar
  11. 11.
    Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3:791–800PubMedCrossRefGoogle Scholar
  12. 12.
    Bernhagen J, Calandra T, Bucala R (1998) Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features. J Mol Med 76:151–161PubMedCrossRefGoogle Scholar
  13. 13.
    Donnelly SC, Bucala R (1997) Macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease. Mol Med Today 3:502–507PubMedCrossRefGoogle Scholar
  14. 14.
    Sun HW, Bernhagen J, Bucala R, Lolis E (1996) Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A 93:5191–5196PubMedCrossRefGoogle Scholar
  15. 15.
    Degryse B, de Virgilio M (2003) The nuclear protein HMGB1, a new kind of chemokine? FEBS Lett 553:11–17PubMedCrossRefGoogle Scholar
  16. 16.
    Lin SG, Yu XY, Chen YX, Huang XR, Metz C, Bucala R, Lau CP, Lan HY (2000) De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits. Circ Res 87:1202–1208PubMedGoogle Scholar
  17. 17.
    Calandra T, Bernhagen J, Mitchell RA, Bucala R (1994) The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179:1895–1902PubMedCrossRefGoogle Scholar
  18. 18.
    Burger-Kentischer A, Goebel H, Seiler R, Fraedrich G, Schaefer HE, Dimmeler S, Kleemann R, Bernhagen J, Ihling C (2002) Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis. Circulation 105:1561–1566PubMedCrossRefGoogle Scholar
  19. 19.
    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 (2000) Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408:211–216PubMedCrossRefGoogle Scholar
  20. 20.
    Ahn JD, Morishita R, Kaneda Y, Lee SJ, Kwon KY, Choi SY, Lee KU, Park JY, Moon IJ, Park JG, Yoshizumi M, Ouchi Y, Lee IK (2002) Inhibitory effects of novel AP-1 decoy oligodeoxynucleotides on vascular smooth muscle cell proliferation in vitro and neointimal formation in vivo. Circ Res 90:1325–1332PubMedCrossRefGoogle Scholar
  21. 21.
    Chen Z, Sakuma M, Zago AC, Zhang X, Shi C, Leng L, Mizue Y, Bucala R, Simon D (2004) Evidence for a role of macrophage migration inhibitory factor in vascular disease. Arterioscler Thromb Vasc Biol 24:709–714PubMedCrossRefGoogle Scholar
  22. 22.
    Schober A, Bernhagen J, Thiele M, Zeiffer U, Knarren S, Roller M, Bucala R, Weber C (2004) Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein e-deficient mice. Circulation 109:380–385PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz RS, Topol EJ, Serruys PW, Sangiorgi G, Holmes DR Jr. (1998) Artery size, neointima, and remodeling: time for some standards. J Am Coll Cardiol 32:2087–2094PubMedCrossRefGoogle Scholar
  24. 24.
    Bittl JA (1996) Advances in coronary angioplasty. N Engl J Med 335:1290–1302PubMedCrossRefGoogle Scholar
  25. 25.
    Schober A, Weber C (2005) Mechanisms of monocyte recruitment in vascular repair after injury. Antioxid Redox Signal 7:1249–1257PubMedCrossRefGoogle Scholar
  26. 26.
    Schober A, Karshovska E, Zernecke A, Weber C (2006) SDF-1alpha-mediated tissue repair by stem cells: a promising tool in cardiovascular medicine? Trends Cardiovasc Med 16:103–108PubMedCrossRefGoogle Scholar
  27. 27.
    Schober A, Knarren S, Lietz M, Lin EA, Weber C (2003) Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice. Circulation 108:2491–2497PubMedCrossRefGoogle Scholar
  28. 28.
    Schwartz SM, deBlois D, O'Brien ER (1995) The intima. Soil for atherosclerosis and restenosis. Circ Res 77:445–465PubMedGoogle Scholar
  29. 29.
    Schwartz RS, Holmes DR Jr., Topol EJ (1992) The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol 20:1284–1293PubMedCrossRefGoogle Scholar
  30. 30.
    Thiele M, Bernhagen J (2005) Link between macrophage migration inhibitory factor and cellular redox regulation. Antioxid Redox Signal 7:1234–1248PubMedCrossRefGoogle Scholar
  31. 31.
    Schober A, Zernecke A, Liehn EA, von Hundelshausen P, Knarren S, Kuziel WA, Weber C (2004) Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets. Circ Res 95:1125–1133PubMedCrossRefGoogle Scholar
  32. 32.
    Schrans-Stassen BH, Lue H, Sonnemans DG, Bernhagen J, Post MJ (2005) Stimulation of vascular smooth muscle cell migration by macrophage migration inhibitory factor. Antioxid Redox Signal 7:1211–1216PubMedCrossRefGoogle Scholar
  33. 33.
    Korshunov VA, Nikonenko TA, Tkachuk VA, Brooks A, Berk BC (2006) Interleukin-18 and macrophage migration inhibitory factor are associated with increased carotid intima-media thickening. Arterioscler Thromb Vasc Biol 26:295–300PubMedCrossRefGoogle Scholar
  34. 34.
    Pan JH, Sukhova GK, Yang JT, Wang B, Xie T, Fu H, Zhang Y, Satoskar AR, David JR, Metz CN, Bucala R, Fang K, Simon DI, Chapman HA, Libby P, Shi GP (2004) Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 109:3149–3153PubMedCrossRefGoogle Scholar
  35. 35.
    Paigen B, Holmes PA, Mitchell D, Albee D (1987) Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. Atherosclerosis 64:215–221PubMedCrossRefGoogle Scholar
  36. 36.
    Burger-Kentischer A, Gobel H, Kleemann R, Zernecke A, Bucala R, Leng L, Finkelmeier D, Geiger G, Schaefer HE, Schober A, Weber C, Brunner H, Rutten H, Ihling C, Bernhagen J (2006) Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). Atherosclerosis 184:28–38PubMedCrossRefGoogle Scholar
  37. 37.
    Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, Bucala R (2002) Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci U S A 99:345–350PubMedCrossRefGoogle Scholar
  38. 38.
    Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH (1999) A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 190:1375–1382PubMedCrossRefGoogle Scholar
  39. 39.
    Mercer J, Figg N, Stoneman V, Braganza D, Bennett MR (2005) Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice. Circ Res 96:667–674PubMedCrossRefGoogle Scholar
  40. 40.
    Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596PubMedCrossRefGoogle Scholar
  41. 41.
    Herder C, Illig T, Baumert J, Muller M, Klopp N, Khuseyinova N, Meisinger C, Martin S, Thorand B, Koenig W (2008) Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: Results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Atherosclerosis (in press)Google Scholar
  42. 42.
    Boisvert WA, Rose DM, Johnson KA, Fuentes ME, Lira SA, Curtiss LK, Terkeltaub RA (2006) Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol 168:1385–1395PubMedCrossRefGoogle Scholar
  43. 43.
    Zernecke A, Bot I, Talab YD, Shagdarsuren E, Bidzhekov K, Meiler S, Krohn R, Schober A, Sperandio M, Soehnlein O, Bornemann J, Tacke F, Biessen EA, Weber C (2007) Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 102:209–217PubMedCrossRefGoogle Scholar
  44. 44.
    Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R (2003) MIF signal transduction initiated by binding to CD74. J Exp Med 197:1467–1476PubMedCrossRefGoogle Scholar
  45. 45.
    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 (2006) CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 25:595–606PubMedCrossRefGoogle Scholar
  46. 46.
    Roscic-Mrkic B, Fischer M, Leemann C, Manrique A, Gordon CJ, Moore JP, Proudfoot AE, Trkola A (2003) RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement. Blood 102:1169–1177PubMedCrossRefGoogle Scholar
  47. 47.
    Huo Y, Weber C, Forlow SB, Sperandio M, Thatte J, Mack M, Jung S, Littman DR, Ley K (2001) The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest 108:1307–1314PubMedGoogle Scholar
  48. 48.
    Poznansky MC, Olszak IT, Foxall R, Evans RH, Luster AD, Scadden DT (2000) Active movement of T cells away from a chemokine. Nat Med 6:543–548PubMedCrossRefGoogle Scholar
  49. 49.
    Lue H, Thiele M, Franz J, Dahl E, Speckgens S, Leng L, Fingerle-Rowson G, Bucala R, Luscher B, Bernhagen J (2007) Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26:5046–5059PubMedCrossRefGoogle Scholar
  50. 50.
    Hristov M, Zernecke A, Bidzhekov K, Liehn EA, Shagdarsuren E, Ludwig A, Weber C (2007) Importance of CXC chemokine receptor 2 in the homing of human peripheral blood endothelial progenitor cells to sites of arterial injury. Circ Res 100:590–597PubMedCrossRefGoogle Scholar
  51. 51.
    Zernecke A, Schober A, Bot I, von Hundelshausen P, Liehn EA, Mopps B, Mericskay M, Gierschik P, Biessen EA, Weber C (2005) SDF-1alpha/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells. Circ Res 96:784–791PubMedCrossRefGoogle Scholar
  52. 52.
    Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC (1997) The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 185:1455–1465PubMedCrossRefGoogle Scholar
  53. 53.
    Gregory JL, Morand EF, McKeown SJ, Ralph JA, Hall P, Yang YH, McColl SR, Hickey MJ (2006) Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2. J Immunol 177:8072–8079PubMedGoogle Scholar
  54. 54.
    Kong YZ, Yu X, Tang JJ, Ouyang X, Huang XR, Fingerle-Rowson G, Bacher M, Scher LA, Bucala R, Lan HY (2005) Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human atherosclerotic plaques. Atherosclerosis 178:207–215PubMedCrossRefGoogle Scholar
  55. 55.
    Johnson JL, George SJ, Newby AC, Jackson CL (2005) Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc Natl Acad Sci U S A 102:15575–15580PubMedCrossRefGoogle Scholar
  56. 56.
    Kong YZ, Huang XR, Ouyang X, Tan JJ, Fingerle-Rowson G, Bacher M, Mu W, Scher LA, Leng L, Bucala R, Lan HY (2005) Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques. Cardiovasc Res 65:272–282PubMedCrossRefGoogle Scholar
  57. 57.
    Pearce E, Tregouet DA, Samnegard A, Morgan AR, Cox C, Hamsten A, Eriksson P, Ye S (2005) Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction. Circ Res 97:1070–1076PubMedCrossRefGoogle Scholar
  58. 58.
    Schmeisser A, Marquetant R, Illmer T, Graffy C, Garlichs CD, Bockler D, Menschikowski D, Braun-Dullaeus R, Daniel WG, Strasser RH (2005) The expression of macrophage migration inhibitory factor 1alpha (MIF 1alpha) in human atherosclerotic plaques is induced by different proatherogenic stimuli and associated with plaque instability. Atherosclerosis 178:83–94PubMedCrossRefGoogle Scholar
  59. 59.
    Shimizu K, Mitchell RN, Libby P (2006) Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 26:987–994PubMedCrossRefGoogle Scholar
  60. 60.
    Pan JH, Lindholt JS, Sukhova GK, Baugh JA, Henneberg EW, Bucala R, Donnelly SC, Libby P, Metz C, Shi GP (2003) Macrophage migration inhibitory factor is associated with aneurysmal expansion. J Vasc Surg 37:628–635PubMedCrossRefGoogle Scholar
  61. 61.
    Verschuren L, Lindeman JH, van Bockel JH, Abdul-Hussien H, Kooistra T, Kleemann R (2005) Up-regulation and coexpression of MIF and matrix metalloproteinases in human abdominal aortic aneurysms. Antioxid Redox Signal 7:1195–1202PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Andreas Schober
    • 1
  • Jürgen Bernhagen
    • 2
  • Christian Weber
    • 3
    Email author
  1. 1.Cardiology Unit, Medical Policlinic-City Center CampusUniversity of MunichMunichGermany
  2. 2.Department of Biochemistry and Molecular Cell Biology, Institute of BiochemistryRWTH Aachen UniversityAachenGermany
  3. 3.Institute of Molecular Cardiovascular ResearchRWTH Aachen UniversityAachenGermany

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