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; Ch J Hemmer; N Mackman; R Kutob; R Ziegler; M Dietrich; P P Nawroth

doi:10.1055/s-0038-1653723

Thrombosis and Haemostasis, Table of Contents

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

¹The Dept. of Medicine I, Univ. of Heidelberg, Germany

,

Ch J Hemmer

²The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany

,

N Mackman

³The Dept. of Immunol., Scripps Res. Clinic, La Jolla, USA

,

R Kutob

²The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany

,

R Ziegler

¹The Dept. of Medicine I, Univ. of Heidelberg, Germany

,

M Dietrich

²The Dept. of Medicine, Bernhard Nocht Inst. for Tropical Medicine, Hamburg, Germany

,

P P Nawroth

¹The Dept. of Medicine I, Univ. of Heidelberg, Germany

› Author Affiliations

Abstract

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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.

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References

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