Cyclosporine a inhibits tissue factor expression in monocytes/macrophages.
Accelerated coronary atherosclerosis in cardiac allografts is the major limiting factor for long-term survival after heart transplantation. There is growing evidence that activation of the coagulation mechanism is involved in the development of transplant atherosclerosis. Tissue factor (TF) expression by cells of the monocyte/macrophage system may represent an important mechanism underlying the fibrin deposition in the affected vessels. In the present study, we investigated the effect of cyclosporine A (CsA) on the lipopolysaccharide (LPS)-induced procoagulant activity (PCA) in human monocytes/macrophages. CsA exerted a dose-dependent inhibitory effect on LPS-induced monocyte/macrophage PCA, which was identified as TF activity based on functional and immunologic characterization. As shown by reverse transcriptase-polymerase chain reaction, CsA reduced the transcription of the TF gene in LPS-stimulated monocytes/macrophages. Electrophoretic mobility shift assay showed that CsA inhibited the LPS-induced activation of the nuclear factor kappa B (NF-kappa B). As shown by Western blot analysis, CsA treatment decreased the nuclear translocation of NF-kappa B, thereby suggesting the mechanism for the inhibitory effect of CsA on TF induction. Hence, a nonimmunologic effect of CsA may contribute to its successful use in transplant medicine.
Department of Internal Medicine, Justus-Liebig-University Giessen, Germany.
H
H
Hölschermann
F
F
Dürfeld
U
U
Maus
A
A
Bierhaus
K
K
Heidinger
J
J
Lohmeyer
P P
PP
Nawroth
H
H
Tillmanns
W
W
Haberbosch
D001692:Biological Transport / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000209:etiology*; D016572:Cyclosporine / Q000494:pharmacology*; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011183:Postoperative Complications / Q000209:etiology*; D011485:Protein Binding / Q000187:drug effects; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C045071:leukocyte procoagulant activity; D016572:Cyclosporine; D013925:Thromboplastin