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

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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 S1P (−/−)3 -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.

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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

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Acknowledgement

This work was supported by grants of the Deutsche Forschungsgemeinschaft to B.K (Kl 988 3-3 and Kl 988 4-2). The experiments comply with the current German law.

Conflict of interest statement

The authors declare that they have no competing financial interests.

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Authors and Affiliations

  1. Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Königin-Luise-Str. 2 + 4, Berlin, 14195, Germany

    Barbara Nieuwenhuis, Anja Lüth, Monika Schäfer-Korting & Burkhard Kleuser

  2. Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA

    Jerold Chun

  3. Institute of Pharmacology, University of Bern, Bern, Switzerland

    Andrea Huwiler

  4. Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany

    Josef Pfeilschifter

Authors
  1. Barbara Nieuwenhuis
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  2. Anja Lüth
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  7. Burkhard Kleuser
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Correspondence to Burkhard Kleuser.

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Nieuwenhuis, B., Lüth, A., Chun, J. et al. Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P3 in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone. J Mol Med 87, 645–657 (2009). https://doi.org/10.1007/s00109-009-0468-x

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  • DOI: https://doi.org/10.1007/s00109-009-0468-x

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