title: Pimecrolimus increases the expression of interferon-inducible genes that modulate human coronary artery cells proliferation.
abstract: The pharmacodynamics of the loaded compounds defines clinical failure or success of a drug-eluting device. Various limus derivatives have entered clinics due to the observed positive outcome after stent implantation, which is explained by their antiproliferative activity resulting from inhibition of the cytosolic immunophilin FK506-binding protein 12. Although pimecrolimus also binds to this protein, pimecrolimus-eluting stents failed in clinics. However, despite its impact on T lymphocytes little is known about the pharmacodynamics of pimecrolimus in cultured human coronary artery cells. We were able to show that pimecrolimus exerts antiproliferative activity in human smooth muscle and endothelial cells. Furthermore in those cells pimecrolimus induced transcription of interferon-inducible genes which in part are known to modulate cell proliferation. Modulation of gene expression may be part of an interaction between calcineurin, the downstream target of the pimecrolimus/FK506-binding protein 12-complex, and the toll-like receptor 4. In accordance are our findings showing that silencing of toll-like receptor 4 by siRNA in A549 a lung carcinoma cell line reduced the activation of interferon-inducible genes upon pimecrolimus treatment in those cells. Based on our findings we hypothesize that calcineurin inhibition may induce the toll-like receptor 4 mediated activation of type I interferon signaling finally inducing the observed effect in endothelial and smooth muscle cells. The crosstalk of interferon and toll-like receptor signaling may be a molecular mechanism that contributed to the failure of pimecrolimus-eluting stents in humans.
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Hussner
authors.affiliation: Institute of Pharmacology, Center of Drug Absorption and Transport, University Medicine, Ernst Moritz Arndt University Greifswald, Felix-Hausdorff-Strasse 3, 17489 Greifswald, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Sünwoldt
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Isabell
authors.initials: I
authors.lastname: Seibert
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gliesche
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: h.meyerzuschwabedissen@unibas.ch.
authors.forename: Henriette E Meyer
authors.initials: HE
authors.lastname: Zu Schwabedissen
mesh_terms: D019703:Calcineurin / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D015607:Stents / Q000009:adverse effects; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D050791:STAT Transcription Factors; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; C117268:pimecrolimus; D053612:Janus Kinases; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus
keywords: Calcineurin; Interferon-β; Pimecrolimus; Toll-like receptor 4