Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia Signaling Regulates Macrophage Migration Inhibitory Factor (MIF) Expression in Stroke

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in many processes, including cellular responses to ischemia/reperfusion injury in the heart and brain. This study was undertaken to determine whether human MIF expression is induced following cerebral ischemia and its role therein. To examine whether the induction of MIF gene expression was mediated by its transcriptional upregulation, the human MIF gene promoter was cloned and a luciferase assay was used to determine the presence of a hypoxia-responsive region in the human MIF promoter. We found that human MIF promoter activity was significantly upregulated by hypoxia. A functional hypoxia-inducible factor 1α-binding site was identified using an electrophoretic mobility shift assay (EMSA). MIF has a protective effect on cortical neurons under oxygen-glucose deprivation (OGD) treatment. MIF significantly reduced OGD-induced cell death. To determine whether the expression of MIF in the human brain is altered following ischemia, brain sections from 10 stroke patients were examined with an antibody against MIF. Blood vessel endothelial cells in the peri-infarct region of ischemic brain displayed strong MIF immunoreactivity with no MIF immunoreactivity in control brains. Furthermore, we found that treatment of human brain endothelial cells with MIF had no effect on human monocyte adhesion to endothelium. Our study demonstrates that MIF gene expression is altered during stroke and dysregulation of the hypoxia signaling-induced MIF expression plays an important role in neuronal death in stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Amarenco P, Labreuche J (2009) Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 8(5):453–463

    Article  CAS  PubMed  Google Scholar 

  2. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y (1988) Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 318(18):1148–1152

    Article  CAS  PubMed  Google Scholar 

  3. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y (2009) Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119(3):480–486

    Article  PubMed  Google Scholar 

  4. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371(9624):1612–1623

    Article  CAS  PubMed  Google Scholar 

  5. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333(24):1581–1587

    Article  Google Scholar 

  6. International Stroke Trial Collaborative Group (1997) The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 349(9065):1569–1581

    Article  Google Scholar 

  7. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog Drug Res 61:39–78

    CAS  PubMed  Google Scholar 

  8. Man S, Ubogu EE, Ransohoff RM (2007) Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol 17(2):243–250

    Article  CAS  PubMed  Google Scholar 

  9. Thelen M, Stein JV (2008) How chemokines invite leukocytes to dance. Nat Immunol 9(9):953–959

  10. Kuhlmann CR, Librizzi L, Closhen D, Pflanzner T, Lessmann V, Pietrzik CU, de Curtis M, Luhmann HJ (2009) Mechanisms of C-reactive protein-induced blood-brain barrier disruption. Stroke 40(4):1458–1466

    Article  CAS  PubMed  Google Scholar 

  11. Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R, Neumann-Haefelin T, Brandes RP (2007) NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38(11):3000–3006

    Article  CAS  PubMed  Google Scholar 

  12. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106(7):829–838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kisucka J, Chauhan AK, Zhao BQ, Patten IS, Yesilaltay A, Krieger M, Wagner DD (2009) Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis. Blood 113(23):6015–6022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Frenkel D, Huang Z, Maron R, Koldzic DN, Hancock WW, Moskowitz MA, Weiner HL (2003) Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol 171(12):6549–6555

    Article  CAS  PubMed  Google Scholar 

  15. Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, Obrenovitch TP, Contreras TJ (1986) Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 17(2):246–253

    Article  CAS  PubMed  Google Scholar 

  16. Tanaka R, Komine-Kobayashi M, Mochizuki H, Yamada M, Furuya T, Migita M, Shimada T, Mizuno Y, Urabe T (2003) Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 117(3):531–539

    Article  CAS  PubMed  Google Scholar 

  17. Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C (2002) Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 22(3):308–317

    Article  CAS  PubMed  Google Scholar 

  18. Hyman MC, Petrovic-Djergovic D, Visovatti SH, Liao H, Yanamadala S, Bouis D, Su EJ, Lawrence DA, Broekman MJ, Marcus AJ, Pinsky DJ (2009) Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. J Clin Invest 119(5):1136–1149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199

    Article  CAS  PubMed  Google Scholar 

  20. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15(8):946–950

    Article  CAS  PubMed  Google Scholar 

  21. Chou WH, Choi DS, Zhang H, Mu D, McMahon T, Kharazia VN, Lowell CA, Ferriero DM, Messing RO (2004) Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury. J Clin Invest 114(1):49–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Connolly ES Jr, Winfree CJ, Prestigiacomo CJ, Kim SC, Choudhri TF, Hoh BL, Naka Y, Solomon RA, Pinsky DJ (1997) Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke. Circ Res 81(3):304–310

    Article  CAS  PubMed  Google Scholar 

  23. Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, Miyasaka M, Ward PA (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44(9):1747–1751

    Article  CAS  PubMed  Google Scholar 

  24. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991) Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci U S A 88(13):5680–5684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, Chavez JC (2007) Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci 27(23):6320–6332

    Article  CAS  PubMed  Google Scholar 

  26. Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR (1999) Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 11(12):4159–4170

    Article  CAS  PubMed  Google Scholar 

  27. Helton R, Cui J, Scheel JR, Ellison JA, Ames C, Gibson C, Blouw B, Ouyang L, Dragatsis I, Zeitlin S, Johnson RS, Lipton SA, Barlow C (2005) Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci 25(16):4099–4107

    Article  CAS  PubMed  Google Scholar 

  28. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107(1):43–54

    Article  CAS  PubMed  Google Scholar 

  29. Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95(14):7987–7992

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW (2002) Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111(5):709–720

    Article  CAS  PubMed  Google Scholar 

  31. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15(20):2675–2686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275

    Article  CAS  PubMed  Google Scholar 

  33. Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR (1989) Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A 86(19):7522–7526

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3(10):791–800

    Article  CAS  PubMed  Google Scholar 

  35. Bacher M, Meinhardt A, Lan HY, Dhabhar FS, Mu W, Metz CN, Chesney JA, Gemsa D, Donnelly T, Atkins RC, Bucala R (1998) MIF expression in the rat brain: implications for neuronal function. Mol Med 4(4):217–230

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 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(6):1895–1902

    Article  CAS  PubMed  Google Scholar 

  37. Nishihira J, Koyama Y, Mizue Y (1998) Identification of macrophage migration inhibitory factor (MIF) in human vascular endothelial cells and its induction by lipopolysaccharide. Cytokine 10(3):199–205

    Article  CAS  PubMed  Google Scholar 

  38. Yoshida T, Sonozaki H, Cohen S (1973) The production of migration inhibition factor by B and T cells of the guinea pig. J Exp Med 138(4):784–797

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Paralkar V, Wistow G (1994) Cloning the human gene for macrophage migration inhibitory factor (MIF). Genomics 19(1):48–51

    Article  CAS  PubMed  Google Scholar 

  40. Yu CM, Lai KW, Chen YX, Huang XR, Lan HY (2003) Expression of macrophage migration inhibitory factor in acute ischemic myocardial injury. J Histochem Cytochem 51(5):625–631

    Article  CAS  PubMed  Google Scholar 

  41. Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R, Young LH (2008) Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451(7178):578–582

    Article  CAS  PubMed  Google Scholar 

  42. Qi D, Hu X, Wu X, Merk M, Leng L, Bucala R, Young LH (2009) Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. J Clin Invest 119(12):3807–3816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Inacio AR, Bucala R, Deierborg T (2011) Lack of macrophage migration inhibitory factor in mice does not affect hallmarks of the inflammatory/immune response during the first week after stroke. J Neuroinflammation 8:75

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Wang L, Zis O, Ma G, Shan Z, Zhang X, Wang S, Dai C, Zhao J, Lin Q, Lin S, Song W (2009) Upregulation of macrophage migration inhibitory factor gene expression in stroke. Stroke 40(3):973–976

    Article  CAS  PubMed  Google Scholar 

  45. Wu Y, Song W (2013) Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. FASEB J 27(1):208–221

    Article  CAS  PubMed  Google Scholar 

  46. Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A 103(49):18727–18732

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123(1):224–235

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Dorovini-Zis K, Prameya R, Bowman PD (1991) Culture and characterization of microvascular endothelial cells derived from human brain. Lab Invest 64(3):425–436

    CAS  PubMed  Google Scholar 

  49. Arumugam TV, Tang SC, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo DG, Ouyang X, Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP (2007) Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci U S A 104(35):14104–14109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Bacher M, Schrader J, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J (2003) Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol 162(1):11–17

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. 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(5):587–596

    Article  CAS  PubMed  Google Scholar 

  52. Roger T, Ding X, Chanson AL, Renner P, Calandra T (2007) Regulation of constitutive and microbial pathogen-induced human macrophage migration inhibitory factor (MIF) gene expression. Eur J Immunol 37(12):3509–3521

    Article  CAS  PubMed  Google Scholar 

  53. Baugh JA, Gantier M, Li L, Byrne A, Buckley A, Donnelly SC (2006) Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. Biochem Biophys Res Commun 347(4):895–903

    Article  CAS  PubMed  Google Scholar 

  54. Elsby LM, Donn R, Alourfi Z, Green LM, Beaulieu E, Ray DW (2009) Hypoxia and glucocorticoid signaling converge to regulate macrophage migration inhibitory factor gene expression. Arthritis Rheum 60(8):2220–2231

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Bacher M, Deuster O, Aljabari B, Egensperger R, Neff F, Jessen F, Popp J, Noelker C, Reese JP, Al-Abed Y, Dodel R (2010) The role of macrophage migration inhibitory factor in Alzheimer’s disease. Mol Med 16(3–4):116–121

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 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(6448):756–759

    Article  CAS  PubMed  Google Scholar 

  57. Leng L, Wang W, Roger T, Merk M, Wuttke M, Calandra T, Bucala R (2009) Glucocorticoid-induced MIF expression by human CEM T cells. Cytokine 48(3):177–185

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Flamant L, Toffoli S, Raes M, Michiels C (2009) Hypoxia regulates inflammatory gene expression in endothelial cells. Exp Cell Res 315(5):733–747

    Article  CAS  PubMed  Google Scholar 

  59. Simons D, Grieb G, Hristov M, Pallua N, Weber C, Bernhagen J, Steffens G (2011) Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med 15(3):668–678

    Article  CAS  PubMed  Google Scholar 

  60. Amaral FA, Fagundes CT, Guabiraba R, Vieira AT, Souza AL, Russo RC, Soares MP, Teixeira MM, Souza DG (2007) The role of macrophage migration inhibitory factor in the cascade of events leading to reperfusion-induced inflammatory injury and lethality. Am J Pathol 171(6):1887–1893

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Wang J, Tong C, Yan X, Yeung E, Gandavadi S, Hare AA, Du X, Chen Y, Xiong H, Ma C, Leng L, Young LH, Jorgensen WL, Li J, Bucala R (2013) Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation 128(3):225–236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV (2005) Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem 280(21):20493–20502

    Article  CAS  PubMed  Google Scholar 

  63. Li J, Zeng Z, Viollet B, Ronnett GV, McCullough LD (2007) Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke 38(11):2992–2999

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Emmanuel Y, Cochlin LE, Tyler DJ, de Jager CA, David Smith A, Clarke K (2013) Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance. Brain Behav 3(2):134–144

    Article  PubMed Central  PubMed  Google Scholar 

  65. Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad GG, Flavell RA, Davis RJ, Rakic P (2003) A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci U S A 100(25):15184–15189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198(9):1391–1402

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425(6955):307–311

    Article  CAS  PubMed  Google Scholar 

  68. Saccani A, Saccani S, Orlando S, Sironi M, Bernasconi S, Ghezzi P, Mantovani A, Sica A (2000) Redox regulation of chemokine receptor expression. Proc Natl Acad Sci U S A 97(6):2761–2766

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Schonemeier B, Schulz S, Hoellt V, Stumm R (2008) Enhanced expression of the CXCl12/SDF-1 chemokine receptor CXCR7 after cerebral ischemia in the rat brain. J Neuroimmunol 198(1–2):39–45

    Article  PubMed  Google Scholar 

  70. Hu X, Dai S, Wu WJ, Tan W, Zhu X, Mu J, Guo Y, Bolli R, Rokosh G (2007) Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation 116(6):654–663

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Zhang M, Mal N, Kiedrowski M, Chacko M, Askari AT, Popovic ZB, Koc ON, Penn MS (2007) SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J 21(12):3197–3207

    Article  CAS  PubMed  Google Scholar 

  72. 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(8):1455–1465

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. 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(12):1202–1208

    Article  CAS  PubMed  Google Scholar 

  74. 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(3):380–385

    Article  CAS  PubMed  Google Scholar 

  75. 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(11):8072–8079

    Article  CAS  PubMed  Google Scholar 

  76. Cheng Q, McKeown SJ, Santos L, Santiago FS, Khachigian LM, Morand EF, Hickey MJ (2010) Macrophage migration inhibitory factor increases leukocyte-endothelial interactions in human endothelial cells via promotion of expression of adhesion molecules. J Immunol 185(2):1238–1247

    Article  CAS  PubMed  Google Scholar 

  77. Inacio AR, Ruscher K, Leng L, Bucala R, Deierborg T (2011) Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke. J Cereb Blood Flow Metab 31(4):1093–1106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Yili Wu, Fang Cai, Ruitao Wang, and Hong Li for their technical assistance and helpful comments. This work is supported by the Canadian Institutes for Health Research Operating Grant MOP-97825). W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease. S.Z. is the recipient of a NSERC-CGSD scholarship.

Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Odysseus Zis, Si Zhang & Weihong Song

  2. Department of Pathology and Laboratory Medicine, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Katerina Dorovini-Zis

  3. Department of Neurology, Guangdong Neuroscience Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China

    Lijuan Wang

  4. Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Weihong Song

Authors
  1. Odysseus Zis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Si Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katerina Dorovini-Zis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lijuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weihong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weihong Song.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zis, O., Zhang, S., Dorovini-Zis, K. et al. Hypoxia Signaling Regulates Macrophage Migration Inhibitory Factor (MIF) Expression in Stroke. Mol Neurobiol 51, 155–167 (2015). https://doi.org/10.1007/s12035-014-8727-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8727-4

Keywords

Search

Navigation