Journal Article

15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub> inhibits INF-γ-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells

Ulf Panzer, Gunther Zahner, Ulrike Wienberg, Oliver M. Steinmetz, Anett Peters, Jan-Eric Turner, Hans-Joachim Paust, Gunter Wolf, Rolf A. K. Stahl and André Schneider

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 23, issue 12, pages 3776-3785
Published in print December 2008 | ISSN: 0931-0509
Published online July 2008 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfn361
15-Deoxy-Δ12,14-prostaglandin J2 inhibits INF-γ-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells

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Background. Activators of the peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ activators on INF-γ-induced expression of the T cell-attracting chemokines IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11 in mouse mesangial cells.

Methods. INF-γ-treated mesangial cells were cultured in the presence or absence of either the naturally occurring PPARγ ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or synthetic PPARγ 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 PPARγ ligands, dose-dependently inhibited INF-γ-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 PPARγ ligands, on IFN-γ-induced tyrosine phosphorylation of JAK1, JAK2, STAT1 and nuclear STAT1 translocation and DNA binding.

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

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

Journal Article.  4286 words.  Illustrated.

Subjects: Nephrology

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