15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and Ciglitazone Modulate Staphylococcus Aureus-Dependent Astrocyte Activation Primarily Through a PPAR-gamma-independent Pathway

J Neurochem. 2006 Dec;99(5):1389-1402. doi: 10.1111/j.1471-4159.2006.04183.x.

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-gamma (PPAR-gamma) 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-gamma agonists, 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, suppress the production of several pro-inflammatory molecules in S. aureus-stimulated astrocytes including interleukin-1beta 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-gamma-deficient astrocytes, supporting PPAR-gamma-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-gamma pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Astrocytes / microbiology
  • Cells, Cultured
  • Hypoglycemic Agents / pharmacology
  • Inflammation Mediators / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / drug effects
  • Nitric Oxide Synthase Type II / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • Staphylococcus aureus / physiology
  • Thiazolidinediones / pharmacology*
  • Toll-Like Receptor 2 / drug effects
  • Toll-Like Receptor 2 / metabolism

Substances

  • 15-deoxyprostaglandin J2
  • Hypoglycemic Agents
  • Inflammation Mediators
  • PPAR gamma
  • Thiazolidinediones
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Nitric Oxide Synthase Type II
  • Prostaglandin D2
  • ciglitazone