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NDT Advance Access originally published online on July 2, 2008
Nephrology Dialysis Transplantation 2008 23(12):3776-3785; doi:10.1093/ndt/gfn361
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


15-Deoxy-{Delta}12,14-prostaglandin J2 inhibits INF-{gamma}-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells

Ulf Panzer1,*, Gunther Zahner1,*, Ulrike Wienberg1, Oliver M. Steinmetz1, Anett Peters1, Jan-Eric Turner1, Hans-Joachim Paust1, Gunter Wolf2, Rolf A. K. Stahl1 and André Schneider1

1 Medizinische Klinik III, Universitätsklinikum Hamburg Eppendorf, Germany 2 Klinik für Innere Medizin III, Klinikum der Friedrich-Schiller-Universität, Jena, Germany

Correspondence and offprint requests to: Ulf Panzer, Medizinische Klinik III, University of Hamburg, Martinistr 52, 20246 Hamburg, Germany. Tel: +49-40-42803-3908; Fax: +49-40-42803-5186; E-mail: panzer{at}uke.uni-hamburg.de



  Abstract

Background. Activators of the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), originally found to be implicated in lipid metabolism and glucose homeostasis, have been shown to modulate inflammatory responses through interference with cytokine and chemokine production. Given the central role of mesangial cell-derived chemokines in glomerular leukocyte recruitment in human and experimental glomerulonephritis, we studied the influence of natural and synthetic PPAR{gamma} activators on INF-{gamma}-induced expression of the T cell-attracting chemokines IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11 in mouse mesangial cells.

Methods. INF-{gamma}-treated mesangial cells were cultured in the presence or absence of either the naturally occurring PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) or synthetic PPAR{gamma} activators of the glitazone group. Chemokine mRNA and protein expression and activation of the JAK/STAT signalling pathway were analysed.

Results. The 15d-PGJ2, but not synthetic PPAR{gamma} ligands, dose-dependently inhibited INF-{gamma}-induced chemokine gene (mRNA and protein) expression. Combined results from EMSA and western blot analysis revealed the inhibitory ability of 15d-PGJ2, but not of synthetic PPAR{gamma} ligands, on IFN-{gamma}-induced tyrosine phosphorylation of JAK1, JAK2, STAT1 and nuclear STAT1 translocation and DNA binding.

Conclusions. Our results demonstrate that 15d-PGJ2 inhibits INF-{gamma}-induced chemokine expression in mesangial cells by targeting the JAK/STAT signalling pathway. This effect is independent of an interference with PPAR{gamma}.

Keywords: chemokines; CXCR3; glomerulonephritis; mesangial cells; T cells

* These authors contributed equally to the work.

Received for publication: 18.10.07
Accepted in revised form: 4. 6.08


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