15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone modulate Staphylococcus aureus-dependent astrocyte activation primarily through a PPAR-γ-independent pathway

Nirmal K. Phulwani, Douglas L. Feinstein, Vitaliy Gavrilyuk, Candan Akar, Tammy Kielian

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Brain abscesses arise from a focal parenchymal infection by various pathogens, particularly Staphylococcus aureus. We have shown that astrocytes are activated upon exposure to S. aureus and may contribute to the excessive tissue damage characteristic of brain abscess. Therefore, modulating astrocyte activation may facilitate a reduction in brain abscess severity. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists are potent inhibitors of microglial activation; however, the effects of these compounds on S. aureus-dependent astrocyte activation have not yet been examined. Here, we demonstrate that two chemically distinct PPAR-γ agonists, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, suppress the production of several pro-inflammatory molecules in S. aureus-stimulated astrocytes including interleukin-1β and nitric oxide (NO). Interestingly, 15d-PGJ2 attenuated Toll-like receptor 2 (TLR2) and inducible nitric oxide synthase expression, but failed to modulate macrophage inflammatory protein-2 (MIP-2/CXCL2) production, suggesting that 15d-PGJ2 is not a global inhibitor of astrocyte activation. Another novel finding of this study was the fact that both 15d-PGJ2 and ciglitazone were capable of attenuating pre-existing astrocyte activation, indicating their potential benefit in a therapeutic setting. Importantly, 15d-PGJ2 and ciglitazone were still capable of inhibiting S. aureus-induced pro-inflammatory mediator release in PPAR-γ-deficient astrocytes, supporting PPAR-γ-independent effects of these compounds. Collectively, these results suggest that 15d-PGJ2 and ciglitazone exert their anti-inflammatory actions on astrocytes primarily independent of the PPAR-γ pathway.

Original languageEnglish (US)
Pages (from-to)1389-1402
Number of pages14
JournalJournal of Neurochemistry
Volume99
Issue number5
DOIs
StatePublished - Dec 2006

Keywords

  • 15-deoxy-Δ -prostaglandin J2
  • Astrocytes
  • Central nervous system
  • Peroxisome proliferator activated receptor-γ
  • Staphylococcus aureus
  • Thiazolidinedione

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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