Journal of Molecular Medicine

, Volume 87, Issue 6, pp 645–657

Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P3 in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone

  • Barbara Nieuwenhuis
  • Anja Lüth
  • Jerold Chun
  • Andrea Huwiler
  • Josef Pfeilschifter
  • Monika Schäfer-Korting
  • Burkhard Kleuser
Original Article

Abstract

Glucocorticoids (GC) represent the most commonly used drugs for the treatment of acute and chronic inflammatory skin diseases. However, the topical long-term therapy of GC is limited by the occurrence of skin atrophy. Most interestingly, although GC inhibit proliferation of human fibroblasts, they exert a pronounced anti-apoptopic action. In the present study, we further elucidated the molecular mechanism of the GC dexamethasone (Dex) to protect human fibroblasts from programmed cell death. Dex not only significantly alters the expression of the cytosolic isoenzyme sphingosine kinase 1 but also initiated an enhanced intracellular formation of the sphingolipid sphingosine 1-phosphate (S1P). Investigations using S1P3(−/−)-fibroblasts revealed that this S1P-receptor subtype is essential for the Dex-induced cytoprotection. Moreover, we demonstrate that the ATP-binding cassette (ABC)-transporter ABCC1 is upregulated by Dex and may represent a crucial carrier to transport S1P from the cytosol to the S1P3-receptor subtype.

Keywords

Glucocorticoids Dexamethasone Sphingosine kinase Sphingosine 1-phosphate ABC-transporter S1P-receptor subtypes 

Abbreviations

ABC-transporter

ATP-binding cassette transporter

Act

actinomycin D

ASO

antisense-oligonucleotide

BH3

Bcl-2 homology 3 domain

BSA

bovine serum albumin

DMEM

Dulbecco’s modified Eagle’s medium

EDTA

ethylenediaminetetraacetic acid

EGF

epidermal growth factor

FACS

fluorescence-activated cell sorting

FCS

foetal calf serum

cFLIP

FADD-like IL-1β-converting enzyme inhibitory protein

Dex

dexamethasone

FLICE

FADD-like IL-1β-converting enzyme

GC

glucocorticoids

GPCR

G-protein-coupled receptor

GR

glucocorticoid receptor

HEPES

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

IL

interleukin

MKP-1

mapkinase phosphatase 1

NF-κB

nuclear factor k B

ODN

oligonucleotides

PBS

phosphate-buffered saline

PCR

polymerase chain reaction

PDGF

platelet-derived growth factor

PI3K

phosphoinositol-3-kinase

PVDF

polyvinylidene difluoride

SDS

sodium dodecyl sulphate

siRNA

small interfering RNA

SphK

sphingosine kinase

S1P

sphingosine 1-phosphate

TNFα

tumour necrosis factor α

VEGF

vascular endothelial growth factor

Supplementary material

109_2009_468_MOESM1_ESM.pdf (497 kb)
ESM 1(PDF 497 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Barbara Nieuwenhuis
    • 1
  • Anja Lüth
    • 1
  • Jerold Chun
    • 2
  • Andrea Huwiler
    • 3
  • Josef Pfeilschifter
    • 4
  • Monika Schäfer-Korting
    • 1
  • Burkhard Kleuser
    • 1
  1. 1.Institute of Pharmacy, Pharmacology and ToxicologyFreie Universität BerlinBerlinGermany
  2. 2.Department of Molecular Biology, The Scripps Research InstituteLa JollaUSA
  3. 3.Institute of PharmacologyUniversity of BernBernSwitzerland
  4. 4.Pharmazentrum FrankfurtKlinikum der Johann Wolfgang Goethe-UniversitätFrankfurtGermany

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