Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Delta12,14-prostaglandin J2.
OBJECTIVE
15-Deoxy-Delta12,14-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 PPARgamma agonists, such as troglitazone, did not inhibit IL-10 signalling. Treatment with GW9662, a specific PPARgamma antagonist, had no effect on 15d-PGJ2-mediated inhibition of IL-10 signalling even at higher concentrations (50 microM), indicating that 15d-PGJ2 affects the IL-10-induced Jak-STAT signalling pathway via an PPARgamma-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.
Ji
J D
JD
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. jjdjmesy@korae.ac.kr
Kim
H J
HJ
Rho
Y H
YH
Choi
S J
SJ
Lee
Y H
YH
Cheon
H J
HJ
Sohn
J
J
Song
G G
GG
D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D016207:Cytokines; D004268:DNA-Binding Proteins; D008024:Ligands; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016753:Interleukin-10; D015230:Prostaglandin D2