Cyclooxygenase-2 and prostaglandins in articular tissues

Martel‐Pelletier, Johanne; Pelletier, Jean‐Pierre; Fahmi, Hassan

doi:10.1016/s0049-0172(03)00134-3

Cited by 300 publications

(229 citation statements)

References 116 publications

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“…Prostaglandins, particularly PGE 2 , as well as COX-2 and COX-1 (enzymes involved in prostaglandin synthesis) are found in the synovial tissue of RA patients and experimental models of RA (30)(31)(32). Although some in vitro studies suggest an antiinflammatory role for PGE 2 (33), most reports implicate PGE 2 as an important pro-inflammatory agent in RA (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Lemos

Grespan

Vieira

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

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IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN γ production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFNγ but was enhanced by prostaglandin E 2 (PGE 2 ). IL-23-induced IL-17 production was increased by PGE 2 and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFNγ-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNγ but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFα, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFNγ production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Lemos

Grespan

Vieira

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

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“…COX-1 is expressed in most tissues and is responsible for physiological production of PGs. COX-2, in contrast, is almost undetectable under physiological conditions but is strongly induced in response to pro-inflammatory stimuli, growth factors, and mitogens (1)(2)(3).…”

Section: Prostaglandin (Pg)mentioning

confidence: 99%

“…1 E 2 is an important modulator of many physiological and pathophysiological conditions, including cell growth, vascular homeostasis, inflammation, immune regulation, cancer, and arthritis (1,2). The biosynthesis of PGE 2 requires two enzymes.…”

Section: Prostaglandin (Pg)mentioning

confidence: 99%

Activation of Peroxisome Proliferator-activated Receptor γ Inhibits Interleukin-1β-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1

Cheng

Afif

Martel‐Pelletier

et al. 2004

Journal of Biological Chemistry

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104

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Membrane-associated prostaglandin (PG) E 2 synthase-1 (mPGES-1) catalyzes the conversion of PGH 2 to PGE 2 , which contributes to many biological processes. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. Here, we examined the effect of PPAR␥ ligands on interleukin-1␤ (IL-1␤)-induced mPGES-1 expression in human synovial fibroblasts. PPAR␥ ligands 15-deoxy-⌬ 12,14 prostaglandin J 2 (15d-PGJ 2 ) and the thiazolidinedione troglitazone (TRO), but not PPAR␣ ligand Wy14643, dose-dependently suppressed IL-1␤-induced PGE 2 production, as well as mPGES-1 protein and mRNA expression. 15d-PGJ 2 and TRO suppressed IL-1␤-induced activation of the mPGES-1 promoter. Overexpression of wild-type PPAR␥ further enhanced, whereas overexpression of a dominant negative PPAR␥ alleviated, the suppressive effect of both PPAR␥ ligands. Furthermore, pretreatment with an antagonist of PPAR␥, GW9662, relieves the suppressive effect of PPAR␥ ligands on mPGES-1 protein expression, suggesting that the inhibition of mPGES-1 expression is mediated by PPAR␥. We demonstrated that PPAR␥ ligands suppressed Egr-1-mediated induction of the activities of the mPGES-1 promoter and of a synthetic reporter construct containing three tandem repeats of an Egr-1 binding site. The suppressive effect of PPAR␥ ligands was enhanced in the presence of a PPAR␥ expression plasmid. Electrophoretic mobility shift and supershift assays for Egr-1 binding sites in the mPGES-1 promoter showed that both 15d-PGJ 2 and TRO suppressed IL-1␤-induced DNA-binding activity of Egr-1. These data define mPGES-1 and Egr-1 as novel targets of PPAR␥ and suggest that inhibition of mPGES-1 gene transcription may be one of the mechanisms by which PPAR␥ regulates inflammatory responses.

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“…PG synthesis by cytokine-inducible COX-2 influences angiogenesis and inflammation of the synovial membrane in RA (4). In fact, proinflammatory cytokines such as TNF-␣ and IL-1␤ induce COX-2 in RA models (5,6).…”

mentioning

confidence: 99%

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

Jeong

Pokharel

Lim

et al. 2009

The Journal of Immunology

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints and subsequent destruction of cartilage and bone. Inflammatory mediators such as PGs and proinflammatory cytokines contribute to RA progress. Pin1, a peptidyl prolyl isomerase, plays important pathophysiological roles in several diseases, including cancer and neurodegeneration. We found that both Pin1 and cyclooxygenase-2 (COX-2) were highly expressed in ankle tissues of type II collagen-induced RA mice. HTB-94 cells overexpressing Pin1 and primary cultured human chondrocytes showed increased basal expression of proinflammatory proteins (COX-2, inducible NO synthase, TNF-α, and IL-1β). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-κB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-κB, CREB, and C/EBP were consistently activated in chondrocytes overexpressing Pin1. Treatment of RA mice with juglone, a chemical inhibitor of Pin1, significantly reduced RA progress and COX-2 expression in the ankle tissues. Moreover, juglone dose dependently decreased the basal COX-2 expression in primary cultured chondrocytes from RA patients. These results demonstrate that Pin1 induction during RA progress stimulates proinflammatory protein expression by activating NF-κB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.

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Cyclooxygenase-2 and prostaglandins in articular tissues

Cited by 300 publications

References 116 publications

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Activation of Peroxisome Proliferator-activated Receptor γ Inhibits Interleukin-1β-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

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