Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Δ12,14-prostaglandin J2

Jong Dae Ji, H. J. Kim, Y. H. Rho, Sungjae Choi, Young Ho Lee, H. J. Cheon, Jeongwon Sohn, Gwan Gyu Song

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Objectives. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand that activates the peroxisome proliferator-activated receptor (PPAR)-γ, 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 γ (IFN-γ)-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-γ 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 PPARγ agonists, such as troglitazone, did not inhibit IL-10 signalling. Treatment with GW9662, a specific PPARγ 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 PPARγ-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-γ. 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.

Original languageEnglish
Pages (from-to)983-988
Number of pages6
JournalRheumatology
Volume44
Issue number8
DOIs
Publication statusPublished - 2005 Aug 1

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STAT3 Transcription Factor
Interleukin-10
Transcriptional Activation
Peroxisome Proliferator-Activated Receptors
Interferons
Anti-Inflammatory Agents
Mitogen-Activated Protein Kinase Kinases
troglitazone
Inhibition (Psychology)
15-deoxy-delta(12,14)-prostaglandin J2
Protein Kinase C
Cytokines
Extracellular Signal-Regulated MAP Kinases
Dactinomycin
p38 Mitogen-Activated Protein Kinases
Cytoplasmic and Nuclear Receptors
Disease Management
Nuclear Family
Lipid Metabolism
Adipocytes

Keywords

  • 15d-PGJ
  • IL-10
  • Monocytes/macrophages
  • STAT3

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

Cite this

Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Δ12,14-prostaglandin J2. / Ji, Jong Dae; Kim, H. J.; Rho, Y. H.; Choi, Sungjae; Lee, Young Ho; Cheon, H. J.; Sohn, Jeongwon; Song, Gwan Gyu.

In: Rheumatology, Vol. 44, No. 8, 01.08.2005, p. 983-988.

Research output: Contribution to journalArticle

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abstract = "Objectives. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand that activates the peroxisome proliferator-activated receptor (PPAR)-γ, 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 γ (IFN-γ)-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-γ 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 PPARγ agonists, such as troglitazone, did not inhibit IL-10 signalling. Treatment with GW9662, a specific PPARγ 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 PPARγ-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-γ. 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-PGJ, IL-10, Monocytes/macrophages, STAT3",
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AU - Ji, Jong Dae

AU - Kim, H. J.

AU - Rho, Y. H.

AU - Choi, Sungjae

AU - Lee, Young Ho

AU - Cheon, H. J.

AU - Sohn, Jeongwon

AU - Song, Gwan Gyu

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N2 - Objectives. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand that activates the peroxisome proliferator-activated receptor (PPAR)-γ, 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 γ (IFN-γ)-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-γ 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 PPARγ agonists, such as troglitazone, did not inhibit IL-10 signalling. Treatment with GW9662, a specific PPARγ 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 PPARγ-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-γ. 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.

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KW - Monocytes/macrophages

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