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Department of Internal Medicine, Divisions of
*
Cardiology and
Pneumology, Justus-Liebig University, Giessen, Germany; and
Max Planck Research Unit "Enzymology of Protein Folding", Halle, Germany
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-
B. 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-B-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-B 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-B in monocytes and EC. Calcineurin was demonstrated to
regulate NF-B activation at the level of IB
degradation,
because agonist-induced phosphorylation and subsequent degradation of
IB is prevented by Cn inhibitors in monocytes but enhanced in EC.
These data identify Cn as an opposite regulator in generating
transcriptionally active NF-B, and they confirm the presumption that
the ability of Cn to participate in NF-B transactivation is not T
cell specific.
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