Download PDF
Thromb Haemost 2000; 84(02): 216-222
DOI: 10.1055/s-0037-1613999
Review Article
Schattauer GmbH

The Factor VIII Acute Phase Response Requires the Participation of NFκB and C/EBP

Megan Begbie   *
1   From the Department of Pathology, Queen’s University, Kingston, Ontario, Canada
,
Colleen Notley
1   From the Department of Pathology, Queen’s University, Kingston, Ontario, Canada
,
Shawn Tinlin
1   From the Department of Pathology, Queen’s University, Kingston, Ontario, Canada
,
Lisa Sawyer
1   From the Department of Pathology, Queen’s University, Kingston, Ontario, Canada
,
David Lillicrap
1   From the Department of Pathology, Queen’s University, Kingston, Ontario, Canada
› Author AffiliationsMany thanks to Dr. Robert Kisilevsky, John Anscin and Ruth Tan for help with the mouse model. We also thank Leslie Steele for helpful discussion and initial contributions to the development of this project. This project was funded by grants B-3123 from the Heart and Stroke Foundation of Ontario and MT-10912 from the Medical Research Council of Canada. M. B. is funded by a Studentship from the Medical Research Council of Canada. D. L. is a Career Investigator of the Heart and Stroke Foundation of Ontario.
Further Information

Publication History

Received 15 November 1999

Accepted after resubmission 16 March 2000

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

Coagulation Factor VIII is an acute phase protein in humans that has recently been shown to be transcriptionally responsive to interleukin-6. In this study, we have demonstrated that the human Factor VIII promoter is activated in cultured hepatocytes exposed to bacterial lipopolysaccharide (LPS). Deletion analysis has narrowed the LPS-responsive element of the Factor VIII promoter to a small region which contains two C/EBP binding sites and an adjacent NFκB binding site. Mutation of the downstream C/EBP site reduces LPS-responsiveness by ∼50%, while mutation of the NFκB binding site completely eliminates LPS-responsiveness. While binding of C/EBPβ and NFκB is still observed in gel retardation studies using acute phase nuclear extracts and a probe containing mutations to the downstream C/EBP site, neither NFκB nor C/EBP appear to bind to a probe in which the NFκB site has been mutated. Conservation of this region of the Factor VIII promoter in species which exhibit an increase in Factor VIII levels in response to inflammatory stimuli suggests that these transcription factor binding sites are important for normal regulation of the Factor VIII gene under conditions of stress.

Keywords

Factor VIII - inflammation - acute phase - NFκB - C/EBP

* Current Address: Dr. M. Begbie, National Heart and Lung Institute, Imperial College of Science and Technology and Medicine, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK


 

  • References

  • 1 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-54.
    CrossrefPubMedGoogle Scholar
  • 2 Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science 1991; 251: 288-92.
    CrossrefPubMedGoogle Scholar
  • 3 Molitor JA, Walker WH, Doerre S, Ballard DW, Greene W. NF-kappa B: a family of inducible and differentially expressed enhancer-binding proteins in human T cells. Proc Natl Acad Sci USA 1990; 87: 10028-32.
    CrossrefPubMedGoogle Scholar
  • 4 Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 1994; 77: 63-71.
    CrossrefPubMedGoogle Scholar
  • 5 Hawkey CJ, Stirling Y, Chakrabarti R, Brozovic M, Cox AG, Meade TW. Haemostatic changes following surgery. Thromb Res 1983; 32: 223-7.
    CrossrefPubMedGoogle Scholar
  • 6 Rennie JA, Ogston D. Changes in coagulation factor following acute myocardial infarction in man. Haemostasis 1976; 05: 258-64.
    PubMedGoogle Scholar
  • 7 Vaziri ND, Branson HE, Ness R. Changes of coagulation factors IX, VIII, VII, X, and V in nephrotic syndrome. Am J Med Sci 1980; 280: 167-71.
    CrossrefPubMedGoogle Scholar
  • 8 Wyshock EG, Suffredini AF, Parrillo JE, Colman RW. Cofactors V and VIII after endotoxin administration to human volunteers. Thromb Res 1995; 05: 377-89.
    PubMedGoogle Scholar
  • 9 Stirling D, Hannant WA, Ludlum CA. Transcriptional activation of the Factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost 1997; 79: 74-8.
    PubMedGoogle Scholar
  • 10 Gorog DA, Rakhit R, Laffan M, Davies GJ. Raised Factor VIII is associated with coronary thrombotic events. Heart 1998; 80: 415-7.
    CrossrefPubMedGoogle Scholar
  • 11 O’Donnell J, Tuddenham EGD, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated Factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
    CrossrefPubMedGoogle Scholar
  • 13 Kraaijenhagen RA, in’t Anker PS, Koopman MM, Reitsma PH, Prins MH, van den Ende A, Buller HR. High plasma concentration of factor VIIIc is a major risk factor for venous thomboembolism. Thromb Haemost 2000; 83: 5-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 O’Donnell J, Mumford AD, Manning RA, Laffan M. Elevation of FVIII:C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83: 10-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Rosendaal FR. High levels of factor VIII and venous thrombosis. Thromb Haemost 2000; 83: 1-2.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Kawasaki T, Kaida T, Arnout J, Vermylen J, Hoylaerts MF. A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic. Thromb Haemost 1999; 81: 306-11.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 McGlynn LK, Mueller CR, Begbie M, Notley CR, Lillicrap DP. Role of the liver-enriched transcription factor hepatocyte nuclear factor-1 in transcriptional regulation of the factor VIII gene. Mol Cell Biol 1996; 16: 1936-45.
    CrossrefPubMedGoogle Scholar
  • 18 Zhang D, Jiang S-L, Rzewnicki D, Samols D, Kushner I. The effect of interleukin 1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem 1995; 310: 143-8.
    CrossrefPubMedGoogle Scholar
  • 19 von Clauss A. Gerinnungphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
    CrossrefPubMedGoogle Scholar
  • 20 Maire P, Wuarin J, Schibler U. The role of cis-acting promoter elements in tissue-specific albumin gene expression. Science 1989; 244: 343-6.
    CrossrefPubMedGoogle Scholar
  • 21 Gutierrez-Ruiz MC, Quiroz SC, Souza V, Bucio L, Hernandez E, Olivares IP, Llorente L, Vargas-Vorackova F, Kershenobich D. Cytokines, growth factors, and oxidative stress in HepG2 cells treated with ethanol, acetaldehyde, and LPS. Toxicology 1999; 134: 197-207.
    CrossrefPubMedGoogle Scholar
  • 22 Figueiredo MS, Brownlee GG. cis-acting elements and transcription factors involved in the promoter activity of the human Factor VIII gene. J Biol Chem 1995; 270: 11828-38.
    CrossrefPubMedGoogle Scholar
  • 23 Dalmon J, Laurent M, Cortois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor I-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13: 1183-93.
    CrossrefPubMedGoogle Scholar
  • 24 Lindhorst E, Young D, Bagshaw W, Hyland M, Kisilevskys R. Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse. Biochim Biophys Acta 1997; 1339: 143-54.
    CrossrefPubMedGoogle Scholar
  • 25 Prasse KW, Topper MJ, Moore JN, Welles EG. Analysis of hemostasis in horses with colic. J Am Vet Med Assoc 1993; 203: 685-93.
    PubMedGoogle Scholar
  • 26 Topper MJ, Prasse KW. Analysis of coagulation proteins as acute-phase reactants in horses with colic. Am J Vet Res 1998; 59: 542-5.
    PubMedGoogle Scholar
  • 27 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM. Characterization of the human Factor VIII gene. Nature 1984; 312: 326-30.
    CrossrefPubMedGoogle Scholar
  • 28 Cameron C, Notley C, Hoyle S, McGlynn L, Hough C, Kamisue S, Giles A, Lillicrap D. The canine Factor VIII cDNA and 5’ flanking sequence. Thromb Haemost 1998; 79: 317-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Healey JF, Lubin IM, Lollar P. The cDNA and derived amino acid sequence of porcine factor VIII. Blood 1996; 88: 4209-14.
    PubMedGoogle Scholar
  • 30 Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA. Genomics 1993; 16: 374-9.
    CrossrefPubMedGoogle Scholar
  • 31 Stein B, Cogswell PC, Baldwin Jr AS. Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction. Mol Cell Biol 1993; 13: 3964-74.
    CrossrefPubMedGoogle Scholar
  • 32 Wion KL, Kelly D, Summerfield JA, Tuddenham EGD, Lawn RM. Distribution of Factor VIII mRNA and antigen in human liver and other tissues. Nature 1985; 317: 726-8.
    CrossrefPubMedGoogle Scholar
  • 33 Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodny OA, Kolpakov FA, Podkolodny NL, Kolchanov NA. Databases on transcriptional regulation: TRANSFAC, TRRD, and COMPEL. Nucleic Acids Res 1998; 26: 364-70.
    PubMedGoogle Scholar
  • 34 Stein B, Baldwin Jr AS. Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B. Mol Cell Biol 1993; 13: 7191-8.
    CrossrefPubMedGoogle Scholar
  • 35 Ray A, Hannink M, Ray BK. Concerted participation of NFkappaB and C/EBP heteromer in lipopolysaccharide induction of serum amyloid A gene expression in liver. J Biol Chem 1995; 270: 7365-74.
    CrossrefPubMedGoogle Scholar
  • 36 Betts JC, Cheshire JK, Akira S, Kishimoto T, Woo P. The role of NFkappa B and NF-IL6 transactivating factors in the synergistic activation of human serum amyloid A gene expression by interleukin-1 and interleukin-6. J Biol Chem 1993; 268: 25624-31.
    PubMedGoogle Scholar
  • 37 Rosendaal FR, Briët E, Stibbe J, van Herpen G, Leuven JA, Hofman A, Vandenbroucke JP. Haemophilia protects against ischaemic heart disease: a study of risk factors. Brit J Haematol 1990; 75: 525-30.
    CrossrefPubMedGoogle Scholar