15-deoxy-Delta12,14-prostaglandin J2 inhibits INF-gamma-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells.
BACKGROUND
Activators of the peroxisome proliferator-activated receptor gamma (PPARgamma), 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 PPARgamma 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 PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or synthetic PPARgamma activators of the glitazone group. Chemokine mRNA and protein expression and activation of the JAK/STAT signalling pathway were analysed.


RESULTS
The 15d-PGJ(2), but not synthetic PPARgamma 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-PGJ(2), but not of synthetic PPARgamma ligands, on IFN-gamma-induced tyrosine phosphorylation of JAK1, JAK2, STAT1 and nuclear STAT1 translocation and DNA binding.


CONCLUSIONS
Our results demonstrate that 15d-PGJ(2) inhibits INF-gamma-induced chemokine expression in mesangial cells by targeting the JAK/STAT signalling pathway. This effect is independent of an interference with PPARgamma.
Panzer
Ulf
U
Medizinische Klinik III, University of Hamburg, Hamburg, Germany. panzer@uke.uni-hamburg.de
Zahner
Gunther
G
Wienberg
Ulrike
U
Steinmetz
Oliver M
OM
Peters
Anett
A
Turner
Jan-Eric
JE
Paust
Hans-Joachim
HJ
Wolf
Gunter
G
Stahl
Rolf A K
RA
Schneider
André
A
D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics* / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000209:etiology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D002839:Chromans; C485433:Cxcl10 protein, mouse; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D045162:Thiazolidinediones; D007371:Interferon-gamma; D053612:Janus Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone