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Interaction of macrophage migration inhibitory factor with ceruloplasmin: role of labile copper ions

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Abstract

Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is a target for pharmacological treatment of sepsis and malignant tumors. Inhibition of tautomerase activity of MIF in reaction with p-hydroxyphenylpyruvate (HPP) was observed in the presence of ceruloplasmin (CP), a copper-containing plasma protein. Binding labile copper ions to CP (CP+Cu(II)) is a prerequisite for MIF inhibiting. CP+Cu(II) is shown to be an uncompetitive inhibitor of MIF (Ki ~ 37 nM), which suggests formation of a complex ‘MIF-HPP-CP-Cu(II)’. Filtration of CP+Cu(II) on a column with Chelex-100, otherwise the presence of high concentrations of histidine, cysteine or methionine abrogated the inhibitory effect of CP. Adding salts of Co(II) and Ni(II) that replace copper ions in the labile sites prevented the inhibitory effect of CP+Cu(II). Limited proteolysis of CP by thrombin diminished its oxidase activity in reaction with p-phenylenediamine, but endowed it with the capacity of inhibiting MIF. Covalent modification of MIF by phenylmethylsulfonyl fluoride (PMSF) resulted in binding of MIF-PMSF to CP immobilized on CM5 chip, the dissociation constant being 4.2 μM. In d-galactosamine-sensitized mice CP+Cu(II) increased the LPS-induced lethality from 54 to 100 %, while administration of antibodies against MIF prevented the lethal effect. The enhancement by CP+Cu(II) of the pro-inflammatory signal of MIF is discussed.

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Abbreviations

CP:

Ceruloplasmin

CP+Cu(II):

Ceruloplasmin with labile copper

HPP:

p-Hydroxyphenylpyruvate

LPS:

Lipopolysaccharide

MIF:

Macrophage migration inhibitory factor

SPR:

Surface plasmon resonance

DEPC:

Diethylpyrocarbonate

References

  • Angeli A, Masera RG, Sartori ML et al (1999) Modulation by cytokines of glucocorticoid action. Ann N Y Acad Sci 876:210–220

    Article  CAS  PubMed  Google Scholar 

  • Bloom BR, Bennet B (1966) Mechanism of reaction in vitro associated with delayed-type hypersensitivity. Science 153:80–82

    Article  CAS  PubMed  Google Scholar 

  • Bozza M, Satoskar AR, Lin G et al (1999) Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 189:341–346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Crichlow GV, Lubetsky JB, Leng L et al (2009) Structural and kinetic analyses of macrophage migration inhibitory factor active site interactions. Biochemistry 48:132–139

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • David JR (1966) Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci USA 56:72–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Denkinger CM, Metz C, Fingerle-Rowson G et al (2004) Macrophage migration inhibitory factor and its role in autoimmune diseases. Arch Immunol Ther Exp (Warsz) 52:389–400

    CAS  Google Scholar 

  • Fingerle-Rowson G, Kaleswarapu DR, Schlander C et al (2009) A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation. Mol Cell Biol 29:1922–1932

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fling SP, Gregerson DS (1986) Peptide and protein molecular weigth determination by electrophoresis using a high-molarity tris buffer system without urea. Anal Biochem 155:83–88

    Article  CAS  PubMed  Google Scholar 

  • Gitlin JD (1988) Transcriptional regulation of ceruloplasmin gene expression during inflammation. J Biol Chem 263:6281–6287

    CAS  PubMed  Google Scholar 

  • Guillen C, McInnes IB, Vaughan D et al (2000) The effects of local administration of lactoferrin on inflammation in murine autoimmune and infectious arthritis. Arthritis Rheum 43:2073–2080

    Article  CAS  PubMed  Google Scholar 

  • Kim IG, Park SY (1998) Requirement of intact human ceruloplasmin for the glutathione-linked peroxidase activity. FEBS Lett 437:293–296

    Article  CAS  PubMed  Google Scholar 

  • Kleemann R, Kapurniotu A, Frank RW et al (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 280:85–102

    Article  CAS  PubMed  Google Scholar 

  • Kleemann R, Kapurniotu A, Mischke R et al (1999) Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81Ser MIF. Eur J Biochem 261:753–766

    Article  CAS  PubMed  Google Scholar 

  • Lindley PF, Card G, Zaitseva I et al (1997) An X-ray structural study of human ceruloplasmin in relation to ferroxidase activity. J Biol Inorg Chem 2:454–463

    Article  CAS  Google Scholar 

  • Lolis E, Bucala R (2003) Macrophage migration inhibitory factor. Expert Opin Ther Targets 7:153–164

    Article  CAS  PubMed  Google Scholar 

  • Martin F, Linden T, Katschinski DM et al (2005) Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood 105:4613–4619

    Article  CAS  PubMed  Google Scholar 

  • Mazumder B, Mukhopadhyay CK, Prok A et al (1997) Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells. J Immunol 159:1938–1944

    CAS  PubMed  Google Scholar 

  • Meyer-Siegler KL, Iczkowski KA, Vera PL (2006) Macrophage migration inhibitory factor is increased in the urine of patients with urinary tract infection: macrophage migration inhibitory factor-protein complexes in human urine. J Urol 175:1523–1528

    Article  CAS  PubMed  Google Scholar 

  • Mozetic-Francky B, Cotic V, Ritonja A et al (1997) High-yield expression and purification of recombinant human macrophage migration inhibitory factor. Protein Expr Purif 9:115–124

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay CK, Mazumder B, Lindley PF et al (1997) Identification of the prooxidant site of human ceruloplasmin: a model for oxidative damage by copper bound to protein surfaces. Proc Natl Acad Sci USA 94:11546–11551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mukhopadhyay CK, Mazumder B, Fox PL (2000) Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275:21048–21054

    Article  CAS  PubMed  Google Scholar 

  • Noyer M, Dwulet FE, Hao YL et al (1980) Purification and characterization of undegraded human ceruloplasmin. Anal Biochem 102:450–458

    Article  CAS  PubMed  Google Scholar 

  • Osaki S (1966) Kinetic studies of ferrous ion oxidation with crystalline human ferroxidase (ceruloplasmin). J Biol Chem 241:5053–5059

    CAS  PubMed  Google Scholar 

  • Panasenko OM, Chekanov AV, Vlasova II et al (2008) A study of the effect of ceruloplasmin and lactoferrin on the chlorination activity of leukocytic myeloperoxidase using the chemiluminescence method. Biofizika 53:573–581

    CAS  PubMed  Google Scholar 

  • Petrovsky N, Bucala R (2000) Macrophage migration inhibitory factor (MIF). A critical neurohumoral mediator. Ann N Y Acad Sci 917:665–671

    Article  CAS  PubMed  Google Scholar 

  • Prozorovski VN, Rashkovetski LG, Vasiliev VB et al (1982) Evidence that human ceruloplasmin molecule consists of homologous parts. Int J Pept Protein Res 19:40–53

    Article  CAS  PubMed  Google Scholar 

  • Roger T, Froidevaux C, Martin C et al (2003) Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4). J Endotoxin Res 9:119–123

    Article  CAS  PubMed  Google Scholar 

  • Samygina VR, Sokolov AV, Pulina MO et al (2008) X-ray diffraction study of highly purified human ceruloplasmin. Crystallogr Rep 53:655–662

    Article  CAS  Google Scholar 

  • Samygina VR, Sokolov AV, Bourenkov G et al (2013) Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins. PLoS One 8:e67145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seshadri V, Fox PL, Mukhopadhyay CK (2002) Dual role of insulin in transcriptional regulation of the acute phase reactant ceruloplasmin. J Biol Chem 277:27903–27911

    Article  CAS  PubMed  Google Scholar 

  • Shiva S, Wang X, Ringwood LA et al (2006) Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2:486–493

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Zakharova ET, Shavlovskiĭ MM et al (2005) Isolation of stable human ceruloplasmin and its interaction with salmon protamine. Bioorg Khim 31:269–279

    CAS  PubMed  Google Scholar 

  • Sokolov AV, Pulina MO, Ageeva KV et al (2007) Identification of leukocyte cationic proteins that interact with ceruloplasmin. Biochemistry (Mosc) 72:872–877

    Article  CAS  Google Scholar 

  • Sokolov AV, Ageeva KV, Pulina MO et al (2008) Ceruloplasmin and myeloperoxidase in complex affect the enzymatic properties of each other. Free Radic Res 42:989–998

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Ageeva KV, Pulina MO et al (2009a) Effect of lactoferrin on oxidative features of ceruloplasmin. Biometals 22:521–529

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Pulina MO, Ageeva KV et al (2009b) Identification of complexes formed by ceruloplasmin with matrix metalloproteinases 2 and 12. Biochemistry (Mosc) 74:1388–1392

    Article  CAS  Google Scholar 

  • Sokolov AV, Ageeva KV, Kostevich VA et al (2010a) Study of interaction of ceruloplasmin with serprocidins. Biochemistry (Mosc) 75:1361–1367

    Article  CAS  Google Scholar 

  • Sokolov AV, Golenkina EA, Kostevich VA et al (2010b) Interaction of ceruloplasmin and 5-lipoxygenase. Biochemistry (Mosc) 75:1464–1469

    Article  CAS  Google Scholar 

  • Sokolov AV, Kostevich VA, Romanico DN et al (2012a) Two-stage method for purification of ceruloplasmin based on its interaction with neomycin. Biochemistry (Mosc) 77:631–638

    Article  CAS  Google Scholar 

  • Sokolov AV, Solovyov KV, Kostevich VA et al (2012b) Protection of ceruloplasmin by lactoferrin against hydroxyl radicals is pH dependent. Biochem Cell Biol 90:397–404

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Acquasaliente L, Kostevich VA et al (2015a) Thrombin inhibits the anti-myeloperoxidase and ferroxidase functions of ceruloplasmin: relevance in rheumatoid arthritis. Free Radic Biol Med. doi: 10.1016/j.freeradbiomed.2015.05.016

  • Sokolov AV, Kostevich VA, Zakharova ET et al (2015b) Interaction of ceruloplasmin with eosinophil peroxidase as compared to its interplay with myeloperoxidase: reciprocal effect on enzymatic properties. Free Radic Res 49:800–811

    Article  CAS  PubMed  Google Scholar 

  • Squitti R, Quattrocchi CC, Salustri C, Rossini PM (2008) Ceruloplasmin fragmentation is implicated in ‘free’ copper deregulation of Alzheimer’s disease. Prion 2:23–27

    Article  PubMed Central  PubMed  Google Scholar 

  • Stoj C, Kosman DJ (2003) Cuprous oxidase activity of yeast Fet3p and human ceruloplasmin: implication for function. FEBS Lett 554:422–426

    Article  CAS  PubMed  Google Scholar 

  • Suarez-Almazor ME, Spooner C, Belseck E (2000) Penicillamine for treating rheumatoid arthritis. Cochrane Database Syst Rev (4):CD001460

  • Vasilyev VB, Kachurin AM, Soroka NV (1988) Dismutation of superoxide radicals by ceruloplasmin—details of the mechanism. Biokhimiya 53:2051–2058

    Google Scholar 

  • Vassiliev V, Harris ZL, Zatta P (2005) Ceruloplasmin in neurodegenerative diseases. Brain Res Brain Res Rev 49:633–640

    Article  CAS  PubMed  Google Scholar 

  • Voronina OV, Monakhov NK (1980) Estradiol-induced formation of the polyribosomal complex synthesizing ceruloplasmin in rats. Biokhimiia 45:1010–1016

    CAS  PubMed  Google Scholar 

  • Waeber G, Calandra T, Bonny C, Bucala R (1999) A role for the endocrine and pro-inflammatory mediator MIF in the control of insulin secretion during stress. Diabetes Metab Res Rev 15:47–54

  • Willson DF (2003) Cytokine pharmasciences licenses anti-MIF technology to Baxter Healthcare Corporation. Cytokine PharmaSciences, Inc

  • Yang S, Hua Y, Nakamura T et al (2006) Up-regulation of brain ceruloplasmin in thrombin preconditioning. Acta Neurochir Suppl 96:203–206

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by RFBR Grants No 13-04-01186, 15-04-03620, 15-54-74006 and by the Program “Human Proteome”. The authors are grateful to Dr. O.Yu. Tretyakov for kindly providing the plasmid that encodes recombinant MIF.

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Authors and Affiliations

  1. Institute for Experimental Medicine, Pavlov Street 12, Saint Petersburg, 197376, Russia

    Valeria A. Kostevich, Alexey V. Sokolov, Natalia A. Grudinina, Elena T. Zakharova & Vadim B. Vasilyev

  2. Research Institute of Physico-Chemical Medicine, ul. Malaya Pirogovskaya 1a, Moscow, 119435, Russia

    Valeria A. Kostevich & Alexey V. Sokolov

  3. Saint Petersburg State University, Mendeleevskaya Line, Saint Petersburg, 199000, Russia

    Alexey V. Sokolov & Vadim B. Vasilyev

  4. Shubnikov Institute of Crystallography of Russian Academy of Sciences, Leninsky pr. 59, Moscow, 117333, Russia

    Valeria R. Samygina

  5. NRC “Kurchatov Institute”, Kurchatov sq. 1, Moscow, 123098, Russia

    Valeria R. Samygina

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  1. Valeria A. Kostevich
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  2. Alexey V. Sokolov
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  4. Elena T. Zakharova
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  5. Valeria R. Samygina
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  6. Vadim B. Vasilyev
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Correspondence to Alexey V. Sokolov.

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Kostevich, V.A., Sokolov, A.V., Grudinina, N.A. et al. Interaction of macrophage migration inhibitory factor with ceruloplasmin: role of labile copper ions. Biometals 28, 817–826 (2015). https://doi.org/10.1007/s10534-015-9868-2

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  • DOI: https://doi.org/10.1007/s10534-015-9868-2

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