CD 14 mediates endotoxin induction of nitric oxide synthase in cultured brain glial cells

Galea, Elena; Reis, Donald J.; Fox, Eben S.; Xu, Hui; Feinstein, Douglas L.

doi:10.1016/0165-5728(95)00143-3

Cited by 73 publications

(38 citation statements)

References 43 publications

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“…LPS stimulates innate immunity by binding to CD14 and perhaps other LPS-binding proteins and activating toll-like receptor 4 (Medzhitov and Janeway 2000). Microglia and astrocytes express CD14 and are activated by LPS in vivo and in vitro (Galea et al 1996;Sugaya et al 1998;Possel et al 2000). Because LPS does not cross the blood-brain barrier, icv LPS injection is a well-established model of activation of innate immunity in brain without recruitment of lymphocytes during the first several days after injection (Montero-Menie et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Montine¹,

Milatović²,

Gupta

et al. 2002

Journal of Neurochemistry

127

143

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Increase in prostaglandin (PG) E 2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE 2 -mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F 2 -isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F 4 -neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F 2 -IsoPs and F 4 -NeuroPs that were completely suppressed by indomethacin or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE 2 (EP 2 ). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre-treatment but was independent of EP 2 receptor activation. The protective effect of deleting the EP 2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP 2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum. Keywords: excitotoxicityinnate immunity, isoprostanes, neuroprostanes, NSAIDs, prostaglandin E 2 . J. Neurochem. Coincident cerebral oxidative damage and elevated prostaglandin (PG) E 2 levels are characteristic of several degenerative and destructive diseases of brain including stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, and Creutzfeldt-Jakob disease (Griffin et al. 1994;Pace and Leaf 1995;Montine et al. 1998Montine et al. , 1999aMontine et al. , 1999bPaoletti et al. 1998;Thornhill and Smith 1998;Minghetti et al. 2000). PGE 2 potently modulates neurodegeneration and oxidative damage in several model systems; however, some have concluded that PGE 2 is neuroprotective while others have proposed that PGE 2 promotes neuronal damage (Akaike et al. 1994;Cazevielle et al. 1994;Minghetti et al. 1997aMinghetti et al. , 1997bMinghetti et al. , 1998Bezzi et al. 1998; Kraig 1998, 1999;Levi et al. 1998;Paoletti et al. 1998;Thornhill and Smith 1998;Aloisi et al. 1999;Kelley et al. 1999;Sanzgiri et al. 1999;Drachman and Rothstein 2000;Hewett et al. 2000). Most in vivo studies suggest that PGE 2 contributes to oxidative damage and neurodegeneration, while most in vitro studies indicate that PGE 2 has neuroprotective activity. There are several possible explanations for these disparate results.Cell culture models typically are limited by use of supraphysiologic concentrations of PGE 2 , by the absence of some of the PGE 2 receptor (EP) subtypes, and by disruption of paracrine interactions between neurons and glia. In vivo studies have rel...

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Section: Discussionmentioning

confidence: 99%

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Montine¹,

Milatović²,

Gupta

et al. 2002

Journal of Neurochemistry

127

143

View full text Add to dashboard Cite

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“…Although astrocytes are capable of cytokine production (278), microglial cells are substantially more responsive to LPS than are astrocytes (195). In contrast to microglial cells from adult brain tissue (357), amoeboid microglial cells express CD14 receptors, which, along with TLR4 (183), are the main plasma membrane binding sites for LPS-induced cytokine expression (117). Although LPS has been used as a classic activating agent, a recent study of rat microglia demonstrated that prolonged LPS exposure induces a distinctly different activated state from that in microglia acutely exposed to LPS (4).…”

Section: Bacteriamentioning

confidence: 99%

Role of Microglia in Central Nervous System Infections

et al. 2004

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The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed

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“…However, involvement of TLR-4 in LPS triggered iNOS upregulation is yet to be experimentally undetermined. On the other hand, the involvement of CD14, a LPS binding glycosylphosphatidylinositol-anchored receptor, is well documented in this regard (46).…”

Section: Bacterial Productsmentioning

confidence: 99%

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells

Saha

Pahan

2006

Antioxidants & Redox Signaling

307

262

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Elevated levels of NO produced within the central nervous system (CNS) are associated with the pathogenesis of neuroinflammatory and neurodegenerative human diseases such as multiple sclerosis, HIV dementia, brain ischemia, trauma, Parkinson's disease, and Alzheimer's disease. Resident glial cells in the CNS (astroglia and microglia) express inducible nitric oxide synthase (iNOS) and produce high levels of NO in response to a wide variety of proinflammatory and degenerative stimuli. Although pathways resulting in the expression of iNOS may vary in two different glial cells of different species, the intracellular signaling events required for the expression of iNOS in these cells are slowly becoming clear. Various signaling cascades converge to activate several transcription factors that control the transcription of iNOS in glial cells. The present review summarizes different results and discusses current understandings about signaling mechanisms for the induction of iNOS expression in activated glial cells. A complete understanding of the regulation of iNOS expression in glial cells is expected to identify novel targets for therapeutic intervention in NO-mediated neurological disorders.

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CD 14 mediates endotoxin induction of nitric oxide synthase in cultured brain glial cells

Cited by 73 publications

References 43 publications

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Role of Microglia in Central Nervous System Infections

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells

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CD 14 mediates endotoxin induction of nitric oxide synthase in cultured brain glial cells

Cited by 73 publications

References 43 publications

Neuronal oxidative damage from activated innate immunity is EP2 receptor‐dependent

Neuronal oxidative damage from activated innate immunity is EP2 receptor‐dependent

Role of Microglia in Central Nervous System Infections

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells

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Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent