Cyclopentenone prostaglandins suppress activation of microglia: Down-regulation of inducible nitric-oxide synthase by 15-deoxy-Δ ^12,14 -prostaglandin J ₂

Abstract

Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of activated glia in neurodegeneration. Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions. We examined the inf luence of cyclopentenone prostaglandins and their precursors on activated glia. As models of glial activation, production of inducible nitric-oxide synthase (iNOS) was studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell line BV-2, and IL-1␤-stimulated rat astrocytes. Cyclopentenone prostaglandins were potent inhibitors of iNOS induction and were more effective than their precursors, prostaglandins E 2 and D 2 . 15-Deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) was the most potent prostaglandin among those tested. In activated microglia, 15d-PGJ 2 suppressed iNOS promoter activity, iNOS mRNA, and protein levels. The action of 15d-PGJ 2 does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) because troglitazone, a specific ligand of PPAR␥, was unable to inhibit iNOS induction, and neither troglitazone nor 15d-PGJ 2 could stimulate the activity of a PPAR-dependent promoter in the absence of cotransfected PPAR␥. 15d-PGJ 2 did not block nuclear translocation or DNA-binding activity of the transcription factor NFB, but it did inhibit the activity of an NFB reporter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ 2 may involve interference with NFB transcriptional activity in the nucleus. Thus, our data suggest the existence of a novel pathway mediated by cyclopentenone prostaglandins, which may represent part of a feedback mechanism leading to the cessation of inf lammatory glial responses in the brain.

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

“…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). 15d-PGJ 2 reduced also LPS-induced iNOS protein expression and NO production (Figures 4b and c) as reported previously (Ricote et al, 1998;Petrova et al, 1999). These results suggest that the mechan-ism of the inhibitory effect of PPARa agonists on NO production is different from that of PPARg agonists.…”

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

“…PPARg-independent effects of 15-PGJ 2 have been previously reported in other systems, including chondrocytes, myofibroblasts, mesangial cells, inflammatory cells and cells of the nervous system (Petrova et al, 1999;Castrillo et al, 2000;Rossi et al, 2000;Straus et al, 2000;Boyault et al, 2001;Li et al, 2001;Janabi, 2002;Ward et al, 2002). Several mechanisms have been implicated as responsible for the effects of 15-PGJ 2 on these cells and may also partly explain its antineoplastic properties.…”

“…Negative regulation of the NF-kB pathway through inhibition of IkB kinase (IKK) and abrogation of the DNA binding ability of NF-kB, has emerged as a major pathway of PPARg-independent 15-PGJ 2 activity (Petrova et al, 1999;Castrillo et al, 2000;Rossi et al, 2000;Straus et al, 2000;Boyault et al, 2001;Janabi, 2002;). 15-PGJ 2 -mediated NF-kB inhibition has been linked to downregulation of inducible nitric oxide synthase (iNOS) and abrogation of cyclooxygenase-2 (COX-2) transactivation (Petrova et al, 1999;Castrillo et al, 2000;Rossi et al, 2000;Straus et al, 2000;Boyault et al, 2001;Janabi, 2002). Similarly, Ward et al (2002) recently showed that 15-PGJ 2 exploits PPARg-independent inhibition of NF-kB activation to induce caspase-dependent apoptosis in granulocytes.…”

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

“…In addition to the beneficial effects microglia have in initiating protective immunity against pathogens, when chronically activated, microglia have been implicated in contributing to neuronal cell death associated with neuroinflammatory and neurodegenerative disorders. Petrova et al [41] were the first to report that the PPAR-γ agonist 15d-PGJ 2 inhibited microglial activation. They demonstrated that 15d-PGJ 2 inhibited NO production by the BV-2 mouse microglial cell line.…”