Download PDF
Thromb Haemost 1995; 73(01): 039-048
DOI: 10.1055/s-0038-1653723
Original Article
Coagulation
Schattauer GmbH Stuttgart

Antiparasitic Treatment of Patients with P. falciparum Malaria Reduces the Ability of Patient Serum to Induce Tissue Factor by Decreasing NF-κB Activation

A Bierhaus
1   The Dept. of Medicine I, Univ. of Heidelberg, Germany
,
Ch J Hemmer
2   The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany
,
N Mackman
3   The Dept. of Immunol., Scripps Res. Clinic, La Jolla, USA
,
R Kutob
2   The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany
,
R Ziegler
1   The Dept. of Medicine I, Univ. of Heidelberg, Germany
,
M Dietrich
2   The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany
,
P P Nawroth
1   The Dept. of Medicine I, Univ. of Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Received 29 November 1993

Accepted after resubmission 19 September 1994

Publication Date:
09 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Serum from patients with P. falciparum malaria at day 1 (pretherapy) induces tissue factor (TF) in cultured endothelial cells. TF induction depends on de novo transcription as shown in Nuclear Run On assays. Electrophoretic mobility shift assays demonstrated binding of AP-1 and NF- κB/Rel proteins to their recognition sites in the TF promotor. After therapy (day 28), stimulation of TF antigen by patient serum is reduced by 70%. When serum obtained before and after therapy was compared, a decrease of NF-κB activation was evident. Activation of NF-κB-like proteins was in part dependent on TNFα in patient serum, since a TNFα neutralizing antibody reduced induction of TF transcription and translation and induction of NF-κB-like proteins. Induction of TF activity was suppressed by pDTC, an inhibitor of NF-κB activation. When different promotor constructs of the TF gene were tested, induction was dependent upon the presence of the intact NF-κB-like binding site in the TF promotor. A mutant with deleted NF-κB, but intact AP-1 sites was not inducible. Mutation of the AP-1 sites did not prevent induction, but reduced inducibility by pretherapy serum. Therefore, NF-κB/Rel proteins are responsible for induction of TF transcription by pretherapy serum, but AP-1 is needed for highest inducibility. The effect of antiparasitic therapy on the induction of TF by serum from patients with complicated P. falciparum malaria is dependent on a therapy-mediated loss of activation of NF-κB-like proteins in post-treatment patient serum.

 

  • References

  • 1 Pukrittayakamee S, White NJ, Clemnes R. Activation of the coagulation cascade in P. falciparum malaria. Trans R Soc Trop Med Hyg 1989; 83: 762-766
    CrossrefPubMedSearch in Google Scholar
  • 2 Philipps RE, Warrell DA. The pathophysiology of severe P. falciparum malaria. Parasit Today 1986; 2: 276-281
    PubMedSearch in Google Scholar
  • 3 MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warell DA. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration Am J Pathol 1985; 119: 385-401
    PubMedSearch in Google Scholar
  • 4 Hemmer CJ, Kern P, Holst FG E, Radke KP, Egbrink R, Bierhaus A, Nawroth PP, Dietrich M. Activation of the host response in human P. falciparum malaria: Relation of parasitemia to Tumor Necrosis Factor/ Cachectin, Thrombin-Antithrombin III and Protein C levels. Am J Med 1991; 91: 37-44
    CrossrefPubMedSearch in Google Scholar
  • 5 Hemmer CJ, Bierhaus A, Riedesel Jv, Gabat S, Liliensiek B, Pitronik P, Lin J, Amiral J, Ziegler R, Schieffer S, Kern P, Seitz R, Egbrink R, Dietrich M, Nawroth PP. Elevated Thrombomodulin serum levels as a result of endothelial involvement in P. falciparum malaria. Thromb Haemost 1994; 72: 457-464
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Kern P, Hemmer CJ, van Damme J, Gruss HJ, Dietrich M. Elevated Tumor Necrosis Factor alpha and Interleukin-6 serum levels as markers for complicated P. falciparum malaria. Am J Med 1989; 87: 139-143
    CrossrefPubMedSearch in Google Scholar
  • 7 Scuderi P, Sterling KE, Lam KS, Finley PR, Ryan KJ, Ray CG, Petersen E, Slymen DJ, Salmon SE. Raised levels of Tumor Necrosis Factor in parasitic infections. Lancet 1986; 2: 1364-1365
    PubMedSearch in Google Scholar
  • 8 Hemmer CJ, Kern P, Radtke KP, Egbring RE, Nawroth PP, Dietrich PP. Malaria tropica mit Gerinnungsaktivierung und Nachweis von Tumornekrosefaktor im Serum. Klin Wochenschr 1990; 68: 281-285
    CrossrefPubMedSearch in Google Scholar
  • 9 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by Tumor Necrosis Factor. J Exp Med 1986; 163: 740-745
    CrossrefPubMedSearch in Google Scholar
  • 10 Stern DM, Kaiser E, Nawroth PP. Regulation of the coagulation system by vascular endothelial cells. Hemostasis 1988; 18: 202-214
    PubMedSearch in Google Scholar
  • 11 Nemerson Y. Tissue Factor and Hemostasis. Blood 1988; 71: 1-8
    PubMedSearch in Google Scholar
  • 12 Bach RR. Initiation of coagulation by Tissue Factor. Crit Rev Biochem 1988; 23: 339-397
    PubMedSearch in Google Scholar
  • 13 Jaffe EA, Nachmann RL, Becker CG, Minick CR J. Culture of human endothelial cells. J Clin Invest 1973; 52: 2745-2757
    CrossrefPubMedSearch in Google Scholar
  • 14 Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stem DM. Tumor Necrosis Factor/Cachectin interacts with endothelial cells to induce release of Interleukin-1. J Exp Med 1986; 163: 1363-1375
    CrossrefPubMedSearch in Google Scholar
  • 15 Nawroth PP, Stern DM, Kisiel W, Bach R. Cellular requirements for Tissue Factor generation by bovine aortic endothelial cells in culture. Thromb Res 1985; 40: 677-691
    CrossrefPubMedSearch in Google Scholar
  • 16 Mackman N, Fowler BJ, Edgington TS, Morrissey JH. Functional analysis of the human Tissue Factor promotor and induction by serum. Proc Natl Acad Sei USA 1990; 87: 2254-2258
    CrossrefPubMedSearch in Google Scholar
  • 17 Mackman N, Brand K, Edgington TS. Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor κB binding sites. J Exp Med 1991; 174: 1517-1526
    CrossrefPubMedSearch in Google Scholar
  • 18 Scarpati EM, Wen D, Broze G, Miletich JP, Flandermayer RR, Siegel NR, Sadler E. Human Tissue Factor: cDNA-sequence and chromosome localization of the gene. Biochemistry 1987; 26: 5234-5238
    CrossrefPubMedSearch in Google Scholar
  • 19 Sassone Corsi P, Ransone LJ, Lamph WW, Verma IM. Direct interaction between fos and jun nuclear oncoproteins: role of the leucine zipper domain. Nature 1988; 36: 692-695
    PubMedSearch in Google Scholar
  • 20 Lamph WW, Dwarki VJ, Montminy M, Verma IM. Negative and positive regulation by transcription factor cAMP response element-binding protein is modulated by phosphorylation. Proc Natl Acad Sei USA 1990; 87: 4320-4324
    CrossrefPubMedSearch in Google Scholar
  • 21 Feinberg AP, Vogelstein B. A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983; 1132: 6-13
    PubMedSearch in Google Scholar
  • 22 Chirgwin JM, Przbyla AE, Macdonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 1979; 18: 5294-5299
    CrossrefPubMedSearch in Google Scholar
  • 23 Sawdey M, Podor TJ, Loskutoff DJ. Regulation of type 1 Plasminogen Activator Inhibitor gene expression in cultured bovine aortic endothelial cells. J Biol Chem 1989; 264: 10396-10401
    PubMedSearch in Google Scholar
  • 24 Greenberg ME, Ziff EB. Stimulation of 3T3 cells induces transcription of the c-fos protooncogene. Nature 1984; 311: 433-438
    CrossrefPubMedSearch in Google Scholar
  • 25 Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucl Acids Res 1991; 19: 2499
    CrossrefPubMedSearch in Google Scholar
  • 26 Mandecki W, Hayden M. Laboratory methods: High resolution polyacrylamide gel electrophoresis of oligonucleotides using L-histidine buffer. DNA 1989; 7: 57-62
    PubMedSearch in Google Scholar
  • 27 Lee ME, Dhadly S, Themizer DH, Clifford JA, Yoshizumi M, Quertermous T. Regulation of Endothelin-1 gene expression by Fos and Jun. J Biol Chem 1991; 266: 19034-19039
    PubMedSearch in Google Scholar
  • 28 Lee ME, Bloch KD, Clifford J, Quertermous T. Functional analysis of the Endothelin-1 gene promotor. J Biol Chem 1990; 265: 10446-10450
    PubMedSearch in Google Scholar
  • 29 de Wet J, Wood KV, De Luca M, Helinski DR, Subrami S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol 1987; 7: 725-737
    CrossrefPubMedSearch in Google Scholar
  • 30 Jain VK, Magrath T. A chemiluminescent assay for quantitation of β-galactosidase in the femtogram range: application to quantitation of β-galactosidase in lacZ-transfected cells. Anal Biochem 1991; 199: 119-124
    CrossrefPubMedSearch in Google Scholar
  • 31 Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of NF-kB transcription factor and HIV-1. EMBO J 1991; 10: 2247-2258
    Search in Google Scholar
  • 32 Bierhaus A, Mackman N, Haase M, Ziegler R, Edgington T, Stem DM, Nawroth PP. AP-1 and NF-κB act in concert to mediate Tissue factor induction by TNFα in BAEC. Thromb Haemost 1993; 69 A 1683
    PubMedSearch in Google Scholar
  • 33 Parry GC, Edgington TS, Mackman N. Regulation of the human tissue factor gene in HeLa cells and human umbilical vein endothelial cells. Thromb Haemost 1993; 69: A734
    PubMedSearch in Google Scholar
  • 34 Mackman N, Oeth P. Lipopolysaccharide induction of the tissue factor gene in human monocytic cells is mediated by a member of the REL family of transcription factors. Thromb Haemost 1993; 69: A2347
    PubMedSearch in Google Scholar
  • 35 Conway E, Bach R, Rosenberg R, Konigsberg WH. Tumor Necrosis Factor enhances expression of Tissue Factor mRNA in endothelial cells. Thromb Res 1989; 53: 231-241
    CrossrefPubMedSearch in Google Scholar
  • 36 Oeth PA, Parry G, Kunsch C, Nantermet P, Rosen CA, Mackman N. Lipopolysaccharide induction of Tissue Factor gene expression in monocytic cells is mediated by binding of c-Rel/p65 heterodimers to a κB-like site. Mol Cell Biol 1994; 14: 3772-3781
    CrossrefPubMedSearch in Google Scholar
  • 37 Parry GC N, Mackman N. Cytokine and LPS induction of Tissue Factor gene expression in human endothelial cells is mediated by binding of a c-Rel/p65 complex to a κB-like site. FASEB J 1994; 8: 5902a
    PubMedSearch in Google Scholar
  • 38 Urban MB, Schreck R, Baeuerle PA. NF-κB contacts DNA by a heterodimer of the p50 and p65 subunit. EMBO J 1991; 10: 1817-1825
    PubMedSearch in Google Scholar
  • 39 Shaw G, Kamen R. A conserved AU sequence from the 3’ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46: 659-667
    CrossrefPubMedSearch in Google Scholar
  • 40 Caput D, Beutler B, Hartog K, Thayer R, Brown-Shimer S, Cerami A. Identification of a common nucleotide sequence in the 3’ untranslated region of mRNA molecules specifiying inflammatory mediators. Proc Natl Acad Sci USA 1986; 83: 1670-1674
    CrossrefPubMedSearch in Google Scholar
  • 41 Crossman DC, Carr PD, Tuddenham GD, Pearson JD, Mc Vey JH. The regulation of Tissue Factor mRNA in human endothelial cells in response to endotoxin or phorbol ester. J Biol Chem 1990; 265: 9782-9787
    PubMedSearch in Google Scholar
  • 42 Olliver V, Houssaye S, Ternisien C, Léon A, de Verneuil H, Elbim C, Mackman N, Edgington TS, de Prost D. Endotoxin-induced Tissue Factor messenger RNA in human monocytes is negatively regulated by a cyclic AMP-dependent mechanism. Blood 1993; 81: 973-979
    CrossrefPubMedSearch in Google Scholar
  • 43 Maker JS, Hong Y. A redox switch and phosphorylation are involved in the posttranscriptional up regulation of the Adenosin-Uridine Binding Factor by phorbol ester and ionophore. J Biol Chem 1991; 266: 3167-3171
    PubMedSearch in Google Scholar
  • 44 Drake T, Cheng J, Chang A, Taylor Jr FB. Expression of Tissue Factor, Thrombomodulin and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993; 142: 1458-1463
    PubMedSearch in Google Scholar
  • 45 Taylor Jr FB, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS, Lethal E. coli septic shock is prevented by blocking Tissue Factor with monoclonal antibody. Circ Shock 1991; 33: 127-134
    PubMedSearch in Google Scholar
  • 46 Zhang Y, Deng Y, Luther T, Waldherr P, Ziegler R, Stern DM, Nawroth PP. Tissue Factor dependent clot formation in Meth-A sarcomas. Thromb Haemost 1993; 69: A740
    PubMedSearch in Google Scholar