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PPAR? prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-?B and inhibition of the PKC?/MEK1/2/ERK1/2/AP-1 pathway.

ABSTRACT: Partial or whole-brain irradiation is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year in the United States. Although the exact mechanisms underlying radiation-induced late effects remain unclear, oxidative stress and inflammation are thought to play a critical role. Microglia are key mediators of neuroinflammation. Peroxisomal proliferator-activated receptor (PPAR) ? has been shown to be a potent regulator of anti-inflammatory responses. Thus, we hypothesized that PPAR? activation would modulate the radiation-induced inflammatory response in microglia. Incubating BV-2 murine microglial cells with the PPAR? agonist L-165041 prevented the radiation-induced increase in: (i) intracellular reactive oxygen species generation, (ii) Cox-2 and MCP-1 expression, and (iii) IL-1? and TNF-? message levels. This occurred, in part, through PPAR?-mediated modulation of stress-activated kinases and proinflammatory transcription factors. PPAR? inhibited NF-?B via transrepression by physically interacting with the p65 subunit and prevented activation of the PKC?/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular reactive oxygen species generation. These data support the hypothesis that PPAR? activation can modulate radiation-induced oxidative stress and inflammatory responses in microglia.

SUBMITTER: Schnegg CI

PROVIDER: S-EPMC3341532 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway.

Schnegg Caroline I CI Kooshki Mitra M Hsu Fang-Chi FC Sui Guangchao G Robbins Mike E ME

Free radical biology & medicine 20120303 9

Partial or whole-brain irradiation is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year in the United States. Although the exact mechanisms underlying radiation-induced late effects remain unclear, oxidative stress and inflammation are thought to play a critical role. Micro ...[more]

PMID: 22387176

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Project description:BackgroundWNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia.MethodsMouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [γ-(35)S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways.ResultsAstrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric G(i/o) proteins to reduce cyclic AMP levels and to activate a G(i/o) protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2) axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation.ConclusionsThus, WNT-5A-induced and G protein-dependent signaling to ERK1/2 is important for the regulation of proinflammatory responses in mouse primary microglia cells. We show for the first time that WNT-5A/G protein signaling mediates physiologically important processes in primary mammalian cells with natural receptor and G protein stochiometry. Consequently, WNT-5A emerges as an important means of astrocyte-microglia communication and we, therefore, suggest WNT-5A as a new player in neuroinflammatory conditions, such as neurodegenerative disease, hypoxia, stroke, injury and infection.

Project description:We have previously demonstrated that a stable synthetic analog of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), restores vascular reactivity, blood pressure, and heart rate in endotoxemic rats. The aim of this study was to determine whether decreased renal expression and activity of soluble epoxide hydrolase (sEH), MEK1, ERK1/2, IKK?, I?B-?, and NF-?B as well as systemic and renal proinflammatory cytokine production associated with increased expression and activity of CYP2C23 contributes to the effect of 5,14-HEDGE to prevent hypotension, tachycardia, inflammation, and mortality in response to systemic administration of lipopolysaccharide (LPS). Blood pressure fell by 33 mmHg and heart rate rose by 57 beats/min in LPS (10 mg/kg, i.p.)-treated rats. Administration of LPS also increased mRNA and protein expression of sEH associated with a decrease in CYP2C23 mRNA and protein expression. Increased activity of sEH and p-MEK1, p-ERK1/2, p-I?B-?, NF-?B, and p-NF-?B protein levels as well as TNF-? and IL-8 production by LPS were also associated with a decreased activity of AA epoxygenases. These effects of LPS were prevented by 5,14-HEDGE (30 mg/kg, s.c.; 1 h after LPS). Treatment of endotoxemic mice with 5,14-HEDGE also raised the survival rate of animals from 84% to 98%. A competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, 20-HEDE (30 mg/kg, s.c.; 1 h after LPS) prevented the effects of 5,14-HEDGE on blood pressure, heart rate, expression and/or activity of sEH, CYP2C23, and ERK1/2 as well as TNF-? and IL-8 levels in rats treated with LPS. These results suggest that decreased expression and/or activity of sEH and MEK1/ERK1/2/IKK?/I?B-?/NF-?B pathway as well as proinflammatory cytokine production associated with increased CYP2C23 expression and antiinflammatory mediator formation participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, inflammation, and mortality in the rodent model of septic shock.

Dataset Information

PPAR? prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-?B and inhibition of the PKC?/MEK1/2/ERK1/2/AP-1 pathway.

Publications

PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway.

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