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Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation

Genes & Immunity volume 13, pages 515–522 (2012)Cite this article

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Abstract

Ficolin-1 is a recognition molecule of the lectin complement pathway. The ficolin-1 gene FCN1 is polymorphic, but the functional and clinical consequences are unknown.The concentration of ficolin-1 in plasma and FCN1 polymorphisms in positions −1981 (rs2989727), −791 (rs28909068), −542 (rs10120023), −271 (rs28909976), −144 (rs10117466) and +7918 (rs1071583) were determined in 100 healthy individuals. FCN1 expression by isolated monocytes and granulocytes and ficolin-1 levels in monocyte culture supernatants were assessed in 21 FCN1-genotyped individuals. FCN1 polymorphisms were determined in a cohort of 251 patients with systemic inflammation. High ficolin-1 plasma levels were significantly associated with the minor alleles in position −542 and −144. These alleles were also significantly associated with high FCN1 mRNA expression. The level of ficolin-1 in culture supernatants was significantly higher in individuals homozygous for the minor alleles at positions −542 and −144. Homozygosity for these alleles was significantly associated with fatal outcome in patients with systemic inflammation. None of the other investigated polymorphisms were associated with FCN1 and ficolin-1 expression, concentration or disease outcome. Functional polymorphic sites in the promoter region of FCN1 regulate both the expression and synthesis of ficolin-1 and are associated with outcome in severe inflammation.

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References

  1. Endo Y, Matsushita M, Fujita T . The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol 2011; 43: 705–712.

    Article  CAS  Google Scholar 

  2. Garred P, Honoré C, Ma YJ, Rørvig S, Cowland J, Borregaard N et al. The genetics of ficolins. J Innate Immun 2010; 2: 3–16.

    Article  CAS  Google Scholar 

  3. Hummelshoj T, Thielens NM, Madsen HO, Arlaud GJ, Sim RB, Garred P et al. Molecular organization of human Ficolin-2. Mol Immunol 2007; 44: 401–411.

    Article  CAS  Google Scholar 

  4. Sugimoto R, Yae Y, Akaiwa M, Kitajima S, Shibata Y, Sato H et al. Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J Biol Chem 1998; 273: 20721–20727.

    Article  CAS  Google Scholar 

  5. Ohashi T, Erickson HP . Oligomeric structure and tissue distribution of ficolins from mouse, pig and human. Arch Biochem Biophys 1998; 360: 223–232.

    Article  CAS  Google Scholar 

  6. Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T . Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 2005; 209: 689–697.

    Article  CAS  Google Scholar 

  7. Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P et al. Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 2007; 44: 856–865.

    Article  CAS  Google Scholar 

  8. Honore C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P et al. The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 2007; 56: 1598–1607.

    Article  CAS  Google Scholar 

  9. Gout E, Garlatti V, Smith DF, Lacroix M, Dumestre-Pérard C, Lunardi T et al. Carbohydrate recognition properties of human ficolins: glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 2010; 285: 6612–6622.

    Article  CAS  Google Scholar 

  10. Honore C., Rørvig S, Munthe-Fog L, Hummelshøj T, Madsen HO, Borregaard N et al. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 2008; 45: 2782–2789.

    Article  CAS  Google Scholar 

  11. Hummelshoj T, Fog LM, Madsen HO, Sim RB, Garred P . Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen). Mol Immunol 2008; 45: 1623–1632.

    Article  CAS  Google Scholar 

  12. Kilpatrick DC, Fujita T, Matsushita M . P35, an opsonic lectin of the ficolin family, in human blood from neonates, normal adults, and recurrent miscarriage patients. Immunol Lett 1999; 67: 109–112.

    Article  CAS  Google Scholar 

  13. Hummelshoj T, Munthe-Fog L, Madsen HO, Fujita T, Matsushita M, Garred P et al. Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2. Hum Mol Genet 2005; 14: 1651–1658.

    Article  CAS  Google Scholar 

  14. Munthe-Fog L, Hummelshøj T, Hansen BE, Koch C, Madsen HO, Skjødt K et al. The impact of FCN2 polymorphisms and haplotypes on the Ficolin-2 serum levels. Scand J Immunol 2007; 65: 383–392.

    Article  CAS  Google Scholar 

  15. Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K et al. Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. J Histochem Cytochem 1999; 47: 777–786.

    Article  CAS  Google Scholar 

  16. Lu J, Le Y, Kon OL, Chan J, Lee SH . Biosynthesis of human ficolin, an Escherichia coli-binding protein, by monocytes: comparison with the synthesis of two macrophage-specific proteins, C1q and the mannose receptor. Immunology 1996; 89: 289–294.

    Article  CAS  Google Scholar 

  17. Teh C, Le Y, Lee SH, Lu J . M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 2000; 101: 225–232.

    Article  CAS  Google Scholar 

  18. Liu Y, Endo Y, Iwaki D, Nakata M, Matsushita M, Wada I et al. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 2005; 175: 3150–3156.

    Article  CAS  Google Scholar 

  19. Honore C, Rørvig S, Hummelshøj T, Skjoedt MO, Borregaard N, Garred P et al. Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 2010; 88: 145–158.

    Article  CAS  Google Scholar 

  20. Endo Y, Sato Y, Matsushita M, Fujita T . Cloning and characterization of the human lectin P35 gene and its related gene. Genomics 1996; 36: 515–521.

    Article  CAS  Google Scholar 

  21. Rorvig S, Honore C, Larsson LI, Ohlsson S, Pedersen CC, Jacobsen LC et al. Ficolin-1 is present in a highly mobilizable subset of human neutrophil granules and associates with the cell surface after stimulation with fMLP. J Leukoc Biol 2009; 86: 1439–1449.

    Article  Google Scholar 

  22. Kakinuma Y, Endo Y, Takahashi M, Nakata M, Matsushita M, Takenoshita S et al. Molecular cloning and characterization of novel ficolins from Xenopus laevis. Immunogenetics 2003; 55: 29–37.

    CAS  PubMed  Google Scholar 

  23. Hummelshoj T, Munthe-Fog L, Madsen HO, Garred P . Functional SNPs in the human ficolin (FCN) genes reveal distinct geographical patterns. Mol Immunol 2008; 45: 2508–2520.

    Article  Google Scholar 

  24. Kjeldsen L, Bjerrum OW, Hovgaard D, Johnsen AH, Sehested M, Borregaard N et al. Human neutrophil gelatinase: a marker for circulating blood neutrophils. Purification and quantitation by enzyme linked immunosorbent assay. Eur J Haematol 1992; 49: 180–191.

    Article  CAS  Google Scholar 

  25. Kjeldsen L, Koch C, Arnljots K, Borregaard N . Characterization of two ELISAs for NGAL, a newly described lipocalin in human neutrophils. J Immunol Methods 1996; 198: 155–164.

    Article  CAS  Google Scholar 

  26. Vander Cruyssen B. et al. Polymorphisms in the ficolin 1 gene (FCN1) are associated with susceptibility to the development of rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 1792–1795.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Wittenborn T, Thiel S, Jensen L, Nielsen HJ, Jensenius JC . Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2010; 2: 167–180.

    Article  CAS  Google Scholar 

  29. Kjaer TR, Hansen AG, Sørensen UB, Nielsen O, Thiel S, Jensenius JC et al. Investigations on the pattern recognition molecule M-ficolin: quantitative aspects of bacterial binding and leukocyte association. J Leukoc Biol 2011; 90: 425–437.

    Article  CAS  Google Scholar 

  30. Munthe-Fog L, Hummelshøj T, Ma YJ, Hansen BE, Koch C, Madsen HO et al. Characterization of a polymorphism in the coding sequence of FCN3 resulting in a ficolin-3 (Hakata antigen) deficiency state. Mol Immunol 2008; 45: 2660–2666.

    Article  CAS  Google Scholar 

  31. Schlapbach LJ, Thiel S, Aebi C, Hirt A, Leibundgut K, Jensenius JC et al. M-ficolin in children with cancer. Immunobiology 2011; 216: 633–638.

    Article  CAS  Google Scholar 

  32. Frederiksen PD, Thiel S, Larsen CB, Jensenius JC . M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 2005; 62: 462–473.

    Article  CAS  Google Scholar 

  33. Garred P, Strom J, Quist L, Taaning E, Madsen HO . Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis 2003; 188: 1394–1403.

    Article  CAS  Google Scholar 

  34. Kirschfink M . Controlling the complement system in inflammation. Immunopharmacology 1997; 38: 51–62.

    Article  CAS  Google Scholar 

  35. Ward PA, Gao H . Sepsis, complement and the dysregulated inflammatory response. J Cell Mol Med 2009; 13: 4154–4160.

    Article  CAS  Google Scholar 

  36. Kornblit B, Munthe-Fog L, Madsen HO, Strøm J, Vindeløv L, Garred P et al. Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome. Crit Care 2008; 12: R83.

    Article  Google Scholar 

  37. Bone RC . Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 1992; 268: 3452–3455.

    Article  CAS  Google Scholar 

  38. Reading CL . Theory and methods for immunization in culture and monoclonal antibody production. J Immunol Methods 1982; 53: 261–291.

    Article  CAS  Google Scholar 

  39. Shi YY, He L . SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005; 15: 97–98.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Vibeke Witved and Sandra Færch for excellent technical assistance. This work was supported by Rigshospitalet, The Novo Nordisk Research Foundation, Sven Andersen Research Foundation and the Capital Region of Denmark.

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Authors and Affiliations

  1. Department of Clinical Immunology, Laboratory of Molecular Medicine, Section 7631, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, Copenhagen, Denmark

    L Munthe-Fog, T Hummelshoj, C Honoré, M E Moller, M O Skjoedt, I Palsgaard, H O Madsen & P Garred

  2. Department of Haematology, The Granulocyte Research Laboratory, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, Copenhagen, Denmark

    N Borregaard

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  1. L Munthe-Fog
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  2. T Hummelshoj
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Correspondence to P Garred.

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Munthe-Fog, L., Hummelshoj, T., Honoré, C. et al. Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation. Genes Immun 13, 515–522 (2012). https://doi.org/10.1038/gene.2012.27

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