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Rheumatology Advance Access published online on April 19, 2005
Rheumatology, doi:10.1093/rheumatology/keh657
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 1, 2005
Accepted March 18, 2005

Original Papers

Inhibition of IL-10-induced STAT3 activation by 15-deoxy-{Delta}12,14-prostaglandin J2

J. D. Ji 1*, H. J. Kim 2, Y. H. Rho 1, S. J. Choi 3, Y. H. Lee 3, H. J. Cheon 4, J. Sohn 4, and G. G. Song 3

1 Rheumatology, Korea University Anam Hospital, Seoul, Korea
2 Department of Microbiology and Immunology, Biomedical Science, Korea University, Korea
3 Rheumatology, Korea University Guro Hospital, Seoul, Korea
4 Department of Biochemistry, Korea University College of Medicine, Seoul, Korea

* To whom correspondence should be addressed.
J. D. Ji, E-mail: jjdjmesy{at}korae.ac.kr


  Abstract

Objectives. 15-Deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand that activates the peroxisome proliferator-activated receptor (PPAR)-{gamma}, a member of the nuclear receptor family implicated in the regulation of lipid metabolism and adipocyte differentiation. Recent data have shown that 15d-PGJ2 exerts anti-inflammatory action via inhibition of the interferon {gamma} (IFN-{gamma})-induced Jak-STAT signalling pathway. The anti-inflammatory effect of IL-10 is mediated via activated STAT3 (signal transducer and activator of transcription 3). In this study, we investigated whether 15d-PGJ2 inhibit IL-10-induced STAT activation.

Methods. We used western blotting, flow cytometric analysis and a real-time polymerase chain reaction.

Results. 15d-PGJ2 blocked IL-10-induced STAT1 and STAT3 activation in primary human monocytes, macrophages and THP-1 cells. Inhibition was not specific for IL-10, as induction of STAT activation by IFN-{gamma} and IL-6 was also inhibited by 15d-PGJ2. Inhibition of IL-10 signalling was induced within 1 h after pretreatment of 15d-PGJ2. Other PPAR{gamma} agonists, such as troglitazone, did not inhibit IL-10 signalling. Treatment with GW9662, a specific PPAR{gamma} antagonist, had no effect on 15d-PGJ2-mediated inhibition of IL-10 signalling even at higher concentrations (50 µM), indicating that 15d-PGJ2 affects the IL-10-induced Jak-STAT signalling pathway via an PPAR{gamma}-independent mechanism. Actinomycin D had no effect on 15d-PGJ2-mediated inhibition of IL-10 signalling, indicating that inhibition of IL-10 signalling occurs independently of de novo gene expression. Also, inhibitors of extracellular signal-regulated kinase (ERKs) (PD98059), p38 MAPK (mitogen-activated protein kinase) (SB203580) and protein kinase C (PKC) (GF109203X, calphostin C) had no effect on 15d-PGJ2-mediated inhibition of IL-10 signalling. These results show that MAPKs and PKC are not involved in the inhibition of IL-10 signalling.

Conclusions. We showed that 15d-PGJ2 non-specifically inhibits STAT signalling of the anti-inflammatory cytokine IL-10 as well as the proinflammatory cytokine IFN-{gamma}. These findings indicate the possibility that 15d-PGJ2 can have adverse effects in the management of diseases in which IL-10 plays a critical role in the suppression of inflammation.

Keywords: 15d-PGJ2; IL-10; STAT3; Monocytes/macrophages.
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