Inhibition of IFN-γ-Mediated Inducible Nitric Oxide Synthase Induction by the Peroxisome Proliferator-Activated Receptor γ Agonist, 15-Deoxy-Δ12,14-Prostaglandin J2, Involves Inhibition of the Upstream Janus Kinase/STAT1 Signaling Pathway

Chen, Ching-Wen; Chang, Ying-Hsin; Tsi, Chin-Ju; Lin, Wan-Wan

doi:10.4049/jimmunol.171.2.979

Cited by 61 publications

(50 citation statements)

References 55 publications

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“…PPARg agonists have been shown to decrease NO production and iNOS expression in macrophages (Ricote et al, 1998;Castrillo et al, 2000;Alleva et al, 2002;Chen et al, 2003), and this inhibitory effect seems to take place at a transcriptional level by Figure 7 Effect of lactacystin on ubiquitinated protein levels in J774 macrophages. When indicated, LPS 10 ng ml À1 was added 8 h prior to lactacystin (10 mM).…”

Section: Discussionmentioning

confidence: 99%

“…inhibiting the action of transcription factors NF-kB and STAT1 (Ricote et al, 1998;Chen et al, 2003). There are, however, only two previous reports on the effects of PPARa agonists on iNOS expression and NO production in macrophages showing contradictory results (Colville-Nash et al, 1998;Cernuda-Morolló n et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Since PPARg agonists have been previously reported to inhibit LPS-induced iNOS mRNA expression in macrophages (Ricote et al, 1998;Castrillo et al, 2000;Chen et al, 2003), we wanted to compare the effects of PPARa agonists to those of PPARg agonists. Although PPARa agonists had no effect on iNOS mRNA expression, we saw a marked reduction in LPSinduced iNOS mRNA levels after treatment with 15d-PGJ 2 , a natural ligand of PPARg (Figure 4a).…”

Section: Effects Of Ppara Agonists On Inos Mrna Levels and Activationmentioning

confidence: 99%

“…PPARg agonists have been shown to decrease interferon g-or lipopolysaccharide (LPS)-induced NO production (Ricote et al, 1998;Alleva et al, 2002;Chen et al, 2003) and iNOS expression (Castrillo et al, 2000;Chen et al, 2003). iNOS expression was shown to be modulated at the transcriptional level.…”

Section: Introductionmentioning

confidence: 99%

“…iNOS expression was shown to be modulated at the transcriptional level. PPARg agonists were proposed to inhibit the action of inflammatory transcription factors nuclear factor kappa B (NF-kB), activator protein 1 and signal transducer and activator of transcription 1 (STAT1) (Ricote et al, 1998;Chen et al, 2003). The effects of PPARa agonists on NO production and iNOS expression in macrophages have been less studied (Colville-Nash et al, 1998;Cernuda-Morolló n et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

Leppänen

Sareila

et al. 2007

British J Pharmacology

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Background and purpose: Nitric oxide (NO) production through the inducible nitric oxide synthase (iNOS) pathway is increased in response to pro-inflammatory cytokines and bacterial products. In inflammation, NO has pro-inflammatory and regulatory effects. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear steroid receptor superfamily, regulate not only metabolic but also inflammatory processes. The aim of the present study was to investigate the role of PPARa in the regulation of NO production and iNOS expression in activated macrophages. Experimental approach: The effects of PPARa agonists were investigated on iNOS mRNA and protein expression, on NO production and on the activation of transcription factors NF-kB and STAT1 in J774 murine macrophages exposed to bacterial lipopolysaccharide (LPS). Key results: PPARa agonists GW7647 and WY14643 reduced LPS-induced NO production in a dose-dependent manner as measured by the accumulation of nitrite into the culture medium. However, PPARa agonists did not alter LPS-induced iNOS mRNA expression or activation of NF-kB or STAT1 which are important transcription factors for iNOS. Nevertheless, iNOS protein levels were reduced by PPARa agonists in a time-dependent manner. The reduction was markedly greater after 24 h incubation than after 8 h incubation. Treatment with the proteasome inhibitors, lactacystin or MG132, reversed the decrease in iNOS protein levels caused by PPARa agonists. Conclusions and implications:The results suggest that PPARa agonists reduce LPS-induced iNOS expression and NO production in macrophages by enhancing iNOS protein degradation through the proteasome pathway. The results offer an additional mechanism underlying the anti-inflammatory effects of PPARa agonists.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Ppara Agonists On Inos Mrna Levels and Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

Leppänen

Sareila

et al. 2007

British J Pharmacology

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Molecular mechanisms underlying the inhibition of IFN‐γ‐induced, STAT1‐mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs

Salter

Ramji

2011

J of Cellular Biochemistry

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PPARs and LXRs are ligand-activated transcription factors that are emerging as promising therapeutic targets for limiting atherosclerosis, an inflammatory disorder orchestrated by cytokines. The potent anti-atherogenic actions of these nuclear receptors involve the regulation of glucose and lipid metabolism along with attenuation of the inflammatory response. Similarly, cholesterol-lowering drugs, statins, inhibit inflammation. Unfortunately, the mechanisms underlying such inhibitory actions of these agents in human macrophages are poorly understood and were therefore investigated in relation to IFN-γ, a key pro-atherogenic cytokine, which mediates its cellular effects mainly through STAT1. Simvastatin and PPAR agonists had no effect on the IFN-γ-induced, phosphorylation-mediated activation of STAT1 and its DNA binding but attenuated its ability to activate gene transcription. On the other hand, LXR activators attenuated both DNA binding and trans-activation potential of STAT1 induced by IFN-γ. These studies reveal differences in the mechanism of action of agonists of PPARs (and simvastatin) and LXRs on the IFN-γ-induced, STAT1-mediated gene transcription in human macrophages.

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Cyclopentenone prostaglandins PGA2 and 15-deoxy-?12,14 PGJ2 suppress activation of murine microglia and astrocytes: Implications for multiple sclerosis

Storer

Chavis

et al. 2005

J. Neurosci. Res.

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The cyclopentenone prostaglandin (cPG) 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) has been identified as a potent antiinflammatory agent that is able to inhibit the activation of macrophages and microglia. Additionally, 15d-PGJ(2) is able to ameliorate the clinical manifestations of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Many biological effects of 15d-PGJ(2) have been attributed to the peroxisome proliferator activated receptor-gamma (PPAR-gamma). PGA(2), like 15d-PGJ(2), is a cPG. The aim of this study is to compare the relative effectiveness of these two cPGs in inhibiting the inflammatory response of mouse microglia and astrocytes, two cell types that upon activation may contribute to the pathology of EAE and MS. Purified primary mouse microglia and astrocytes were treated with either 15d-PGJ(2) or PGA(2) and then stimulated with either lipopolysaccharide (LPS) or a combination of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. The results show that 15d-PGJ(2) and PGA(2) both potently inhibited the production of nitrite, as well as proinflammatory cytokines and chemokines, from microglia and astrocytes. Generally, regulation of NO production was more sensitive to 15d-PGJ(2), however, cytokine and chemokine production was more sensitive to PGA(2) treatment. These results demonstrate for the first time that PGA(2) is a potent antiinflammatory mediator.

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Inhibition of IFN-γ-Mediated Inducible Nitric Oxide Synthase Induction by the Peroxisome Proliferator-Activated Receptor γ Agonist, 15-Deoxy-Δ12,14-Prostaglandin J2, Involves Inhibition of the Upstream Janus Kinase/STAT1 Signaling Pathway

Cited by 61 publications

References 55 publications

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

Molecular mechanisms underlying the inhibition of IFN‐γ‐induced, STAT1‐mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs

Cyclopentenone prostaglandins PGA2 and 15-deoxy-?12,14 PGJ2 suppress activation of murine microglia and astrocytes: Implications for multiple sclerosis

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