title: Opposite regulation of tissue factor expression by calcineurin in monocytes and endothelial cells.
abstract: Tissue factor (TF), the primary initiator of blood coagulation with structural homology to the cytokine receptor family, has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Within the vasculature, monocytes and endothelial cells (EC) can be activated to synthesize TF depending on the induction of NF-kappaB. Despite the undisputed value of cyclosporin A (CsA) as an immunosuppressant, problems have emerged due to induction of vascular changes by a poorly understood mechanism. We demonstrate that CsA has opposite effects on TF gene expression, inhibiting NF-kappaB-mediated TF gene transcription in monocytes but enhancing it in EC. To test whether CsA binding proteins (cyclophilins) can mediate these CsA effects we used a nonimmunosuppressant analog of CsA that binds to cyclophilins but does not inhibit the Ca2+/calmodulin-dependent phosphatase calcineurin (Cn). This drug lacked regulatory function for NF-kappaB and TF expression suggesting that Cn is responsible for the inverse gene regulation. The key function of Cn was supported by experiments demonstrating that other phosphatase inhibitors also either positively or negatively regulated NF-kappaB in monocytes and EC. Calcineurin was demonstrated to regulate NF-kappaB activation at the level of IkappaBalpha degradation, because agonist-induced phosphorylation and subsequent degradation of IkappaBalpha is prevented by Cn inhibitors in monocytes but enhanced in EC. These data identify Cn as an opposite regulator in generating transcriptionally active NF-kappaB, and they confirm the presumption that the ability of Cn to participate in NF-kappaB transactivation is not T cell specific.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Justus-Liebig University, Giessen, Germany. hans.f.hoelschermann@innere.med.uni-giessen.de
authors.forename: H
authors.initials: H
authors.lastname: Hölschermann
authors.forename: C
authors.initials: C
authors.lastname: Rascher
authors.forename: C
authors.initials: C
authors.lastname: Oelschläger
authors.forename: G
authors.initials: G
authors.lastname: Stapfer
authors.forename: A
authors.initials: A
authors.lastname: Langenstein
authors.forename: A
authors.initials: A
authors.lastname: Staubitz
authors.forename: U
authors.initials: U
authors.lastname: Maus
authors.forename: H
authors.initials: H
authors.lastname: Tillmanns
authors.forename: H
authors.initials: H
authors.lastname: Bang
authors.forename: W
authors.initials: W
authors.lastname: Haberbosch
mesh_terms: D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014471:Umbilical Veins
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016572:Cyclosporine; D013925:Thromboplastin; D019703:Calcineurin; D019696:Peptidylprolyl Isomerase