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Pimecrolimus increases the expression of interferon-inducible genes that modulate human coronary artery cells proliferation
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3533404
Author(s) Hussner, Janine; Sünwoldt, Juliane; Seibert, Isabell; Gliesche, Daniel G.; Meyer zu Schwabedissen, Henriette E.
Author(s) at UniBasel Meyer zu Schwabedissen, Henriette
Hussner, Janine
Seibert, Isabell
Year 2016
Title Pimecrolimus increases the expression of interferon-inducible genes that modulate human coronary artery cells proliferation
Journal European Journal of Pharmacology
Volume 784
Pages / Article-Number 137-46
Mesh terms Calcineurin, metabolism; Cell Line, Tumor; Cell Proliferation, drug effects; Cell Survival, drug effects; Coronary Vessels, cytology; Endothelial Cells, drug effects; Humans; Interferon-beta, pharmacology; Janus Kinases, metabolism; Myocytes, Smooth Muscle, drug effects; STAT Transcription Factors, metabolism; Signal Transduction, drug effects; Sirolimus, pharmacology; Stents, adverse effects; Tacrolimus, pharmacology; Toll-Like Receptor 4, metabolism; Transcription, Genetic, drug effects; Transcriptional Activation, drug effects
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.
Publisher Elsevier
ISSN/ISBN 0014-2999 ; 1879-0712
edoc-URL http://edoc.unibas.ch/43322/
Full Text on edoc No
Digital Object Identifier DOI 10.1016/j.ejphar.2016.05.020
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/27212382
ISI-Number WOS:000379653600015
Document type (ISI) Journal Article
 
   

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