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Cross-talk between PDGF and S1P signalling elucidates the inhibitory effect and potential antifibrotic action of the immunomodulator FTY720 in activated HSC-cultures

Brunati, AM, Tibaldi, E, Carraro, A, Gringeri, E, D’Amico Jr, F, Toninello, A, Massimino, ML, Pagano, MA, Nalesso, G and Cillo, U (2008) Cross-talk between PDGF and S1P signalling elucidates the inhibitory effect and potential antifibrotic action of the immunomodulator FTY720 in activated HSC-cultures Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1783 (3). pp. 347-359.

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Abstract

Platelet-derived growth factor (PDGF) has been shown to be essential in the activation of hepatic stellate cells (HSCs), contributing to the onset and development of hepatic fibrosis. Recently, sphingosine-1-phosphate (S1P) has been shown to be a mitogen and stimulator of chemotaxis also for HSCs. Since it has been demonstrated in several cell types that cross-talk between PDGF and S1P signalling pathways occurs, our aim was to investigate the potential antifibrotic effect of FTY720, whose phosphorylated form acts as a potent S1P receptor (S1PR) modulator, on HSCs. FTY720 inhibits cell proliferation and migration after PDGF stimulation on HSCs in a concentration range between 0.1 and 1 μM. By using compounds that block S1P signalling (PTX and VPC23019), we assessed that FTY720 also acts in an S1P receptor-independent way by decreasing the level of tyrosine phosphorylation of PDGF receptor, with subsequent inhibition of the PDGF signalling pathway. In addition, inhibition of sphingosine kinase2 (SphK2), which is responsible for FTY720 phosphorylation, by DMS/siRNA unveils a mechanism of action irrespective of its phosphorylation, in particular decreasing the level of S1P1 on the plasma membrane. These findings led us to hypothesize a potential use of FTY720 as a potential antifibrotic drug for further clinical application.

Item Type: Article
Subjects : Veterinary Medicine
Authors :
NameEmailORCID
Brunati, AMUNSPECIFIEDUNSPECIFIED
Tibaldi, EUNSPECIFIEDUNSPECIFIED
Carraro, AUNSPECIFIEDUNSPECIFIED
Gringeri, EUNSPECIFIEDUNSPECIFIED
D’Amico Jr, FUNSPECIFIEDUNSPECIFIED
Toninello, AUNSPECIFIEDUNSPECIFIED
Massimino, MLUNSPECIFIEDUNSPECIFIED
Pagano, MAUNSPECIFIEDUNSPECIFIED
Nalesso, Gg.nalesso@surrey.ac.ukUNSPECIFIED
Cillo, UUNSPECIFIEDUNSPECIFIED
Date : March 2008
Identification Number : https://doi.org/10.1016/j.bbamcr.2007.11.008
Copyright Disclaimer : © 2007 Elsevier B.V. All rights reserved.
Uncontrolled Keywords : Integrative signalling, S1P receptor, PDGF receptor, PTX
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:48
Last Modified : 18 May 2017 12:44
URI: http://epubs.surrey.ac.uk/id/eprint/829286

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