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Rheumatology Advance Access originally published online on April 19, 2005
Rheumatology 2005 44(8):983-988; 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

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

J. D. Ji, H. J. Kim1, Y. H. Rho, S. J. Choi3, Y. H. Lee3, H. J. Cheon2, J. Sohn2 and G. G. Song3

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

Correspondence to: J. D. Ji, Division of Rheumatology, Department of Internal Medicine, College of Medicine, Korea University, 126-1, Anam-dong 5-Ga, Sungbuk-Gu, Seoul 136-705, South Korea. E-mail: jjdjmesy{at}korae.ac.kr

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.

KEY WORDS: 15d-PGJ2, IL-10, STAT3, Monocytes/macrophages


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