Role of the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) and its natural ligand 15‐deoxy‐Δ^12,14‐prostaglandin J₂in the regulation of microglial functions

Abstract

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of a large group of nuclear receptors controlling the proliferation of peroxisomes that is involved in the downregulation of macrophage functions. Here, we report that PPAR-gamma was constitutively expressed in rat primary microglial cultures and that such expression was downregulated during microglial activation by endotoxin (LPS). The presence of the PPAR-gamma natural ligand 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) counteracted the repression of PPAR-gamma expression caused by LPS. In microglial cultures stimulated by LPS, interferon-gamma (IFN-gamma) or by their combination, 15d-PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS). The inhibitory effect was dose-dependent and did not involve an elevation of cyclic AMP, a second messenger known to inhibit NOS expression in microglia. In addition, 15d-PGJ2 down-regulated other microglial functions, such as tumour necrosis factor-alpha (TNF-alpha) synthesis and major histocompatibility complex class II (MHC class II) expression. The effects of 15d-PGJ2 occurred, at least in part, through the repression of two important transcription factors, the signal transducer and activator of transcription 1 and the nuclear factor kappaB, known to mediate IFN-gamma and LPS cell signalling. Our observations suggest that 15d-PGJ2, the synthesis of which is likely to occur within the brain, could play an important role in preventing brain damage associated with excessive microglial activation.

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

“…These studies also suggested that 15d-PGJ 2 does not affect NF-κB nuclear translocation and DNA binding, but does affect the activation of NF-κB-responsive genes, which was proposed to occur through a PPAR-γ-independent mechanism since troglitazone did not have similar effects [41]. Bernardo et al [2] demonstrated that 15d-PGJ 2 suppressed TNF-α, NO, and MHC class II expression by primary microglia. This was proposed to occur through a PPAR-γ-dependent manner since ciglitazone had similar effects.…”

“…The basis for the discrepancy between these studies concerning whether 15d-PGJ 2 influences microglial cell function through PPAR-γ-dependent or -independent mechanisms may be explained by the fact that the Bernardo studies were conducted using primary microglia while the Petrova studies were conducted with BV-2 cells which express little or no PPAR-γ. On the contrary, primary microglia constitutively express this receptor, and the expression is increased in response to 15d-PGJ 2 and suppressed by LPS [2]. Furthermore, PPAR-γ agonists activated the receptor in microglia, resulting in receptor binding to PPREs [1].…”

Microglial Activation in Stroke: Therapeutic Targets

“…169 -172 The anti-inflammatory effect of 15d-PGJ2 is mediated at least in part through suppression of STAT expression and a resultant increase in I B expression, leading to decreased nuclear translocation of NF-B and thus decreased NF-B transcription activity. 169,173 Moreover, at high concentrations 15d-PGJ2 induces apoptosis in activated microglia. 172 Cerebral ischemia increases PPAR␥ expression in neurons and microglia, but at the same time DNA binding of PPAR␥ is reduced.…”

“…167,168 PPAR␥ expression in primary microglia cells is downregulated upon microglial activation, but introduction of the natural ligand, 15d-PGJ2, restores PPAR␥ expression and PPAR␥ DNA binding. 169 Treatment with either natural or synthetic PPAR␥ ligands suppresses iNOS and MHC class II expression, inhibits COX-2 activity, and suppresses synthesis of PGE2, NO, TNF␣, IL-1␤, and IL-6 by cultured microglia. 169 -172 The anti-inflammatory effect of 15d-PGJ2 is mediated at least in part through suppression of STAT expression and a resultant increase in I B expression, leading to decreased nuclear translocation of NF-B and thus decreased NF-B transcription activity.…”

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…The endogenous ligand of PPAR-gamma, 15d-PGJ2, has been shown to directly (without involving PPAR-gamma) prevent microglial and astroglial activation by bacterial endotoxins (53). A recent study also showed that 15d-PGJ2 was unable to activate a PPAR reporter gene transfected into a glial cell line, suggesting that it might act independently of PPAR-gamma activation (22).…”