Contribution of Cyclopentenone Prostaglandins to the Resolution of Inflammation Through the Potentiation of Apoptosis in Activated Macrophages

Abstract

Activation of the macrophage cell line RAW 264.7 with LPS and IFN-γ induces apoptosis through the synthesis of high concentrations of NO due to the expression of NO synthase-2. In addition to NO, activated macrophages release other molecules involved in the inflammatory response, such as reactive oxygen intermediates and PGs. Treatment of macrophages with cyclopentenone PGs, which are synthesized late in the inflammatory onset, exerted a negative regulation on cell activation by impairing the expression of genes involved in host defense, among them NO synthase-2. However, despite the attenuation of NO synthesis, the percentage of apoptotic cells increased with respect to activated cells in the absence of cyclopentenone PGs. Analysis of the mechanisms by which these PGs enhanced apoptosis suggested a potentiation of superoxide anion synthesis that reacted with NO, leading to the formation of higher concentrations of peroxynitrite, a more reactive and proapoptotic molecule than the precursors. The effect of the cyclopentenone 15-deoxy-Δ12,14-PGJ2 on superoxide synthesis was dependent on p38 mitogen-activated protein kinase activity, but was independent of the interaction with peroxisomal proliferator-activated receptor γ. The potentiation of apoptosis induced by cyclopentenone PGs involved an increase in the release of cytochrome c from the mitochondria to the cytosol and in the nitration of this protein. These results suggest a role for cyclopentenone PGs in the resolution of inflammation by inducing apoptosis of activated cells.

Preventive Effect of the Flavonoid, Wogonin, Against Ethanol-Induced Gastric Mucosal Damage in Rats

“…The biosynthesis of PGD 2 does not show significant changes after absolute ethanol ingestion, however, it was significantly elevated by wogonin pretreatment, especially at a dose of 30 mg/kg B. through a definite reduction of neutrophil levels, and involvement of PGD 2 has been proposed in the genesis and recovery of gastric lesions by increasing gastric mucosal blood flow by vasodilation or in apoptosis induction (16)(17)(18). In other experiments, PGD 2 was found to be a very important antiinflammatory mediators, especially in the very early phase of the prevention of propagation of initiated inflammation (19)(20)(21). Moreover, the increase in PGD 2 production paralleled changes in COX-2 expression and was suppressed by a selective COX-2 inhibitor (21).…”

N-Acetylcysteine and 15 Deoxy-Δ12,14-Prostaglandin J2 Exert a Protective Effect Against Autoimmune Thyroid Destruction in Vivo but Not Against Interleukin-1α/Interferon γ-Induced Inhibitory Effects in Thyrocytes in Vitro

“…49 -51 15dPGJ2 may also modulate or inhibit the nuclear factor B system [51][52][53] and activate the mitogen activated protein kinase pathway through PPAR␥-dependent and independent mechanisms. 54 Because 15dPGJ2 has no direct effect on thyroid cells in vitro, but is able to reduce inflammation in vivo, we suggest that 15dPGJ2 may favorably influence OS in the thyroid gland by acting directly on infiltrating inflammatory cells.…”

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

“…Interestingly, B cells express PPAR-γ and the PPAR-γ ligands 15d-PGJ 2 and thiazolidinediones inhibit Bcell proliferation and induce apoptosis of these cells [37,38]. PPAR-γ agonists can also potentiate the apoptosis of macrophages [23]. Collectively, these studies suggest that PPAR-γ may modulate MS in part by stimulating apoptosis of peripheral immune cells.…”