Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Delta 12,14-prostaglandin J(2)

초록

Objectives. 15-Deoxy-Delta 12,14-prostaglandin J(2) (15d-PGJ(2)) 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-PGJ(2) 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-PGJ(2) inhibit IL-10-induced STAT activation. Methods. We used western blotting, flow cytometric analysis and a real-time polymerase chain reaction. Results. 15d-PGJ(2) 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-PGJ(2). Inhibition of IL-10 signalling was induced within 1 h after pretreatment of 15d-PGJ(2). 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-PGJ(2)-mediated inhibition of IL-10 signalling even at higher concentrations (50 mu M), indicating that 15d-PGJ(2) affects the IL-10-induced Jak-STAT signalling pathway via an PPAR gamma-independent mechanism. Actinomycin D had no effect on 15d-PGJ(2)-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-PGJ(2)-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-PGJ(2) 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-PGJ(2) can have adverse effects in the management of diseases in which IL-10 plays a critical role in the suppression of inflammation.

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