Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures

Jeohn, Gwang‐Ho; Kong, Ling-Yuan; Wilson, Belinda; Hudson, Pearlie M.; Hong, Jau–Shyong

doi:10.1016/s0165-5728(97)00204-x

Cited by 185 publications

(109 citation statements)

References 38 publications

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“…In addition to NO, TNF␣ has been suspected to be an important mediator of LPSinduced inflammation, as evidenced by the findings that levels of TNF␣ in the CSF of patients with bacterial meningitis correlate with concentrations of bacterial endotoxin in the brain (Arditi et al, 1990). Although TNF␣ alone is not capable of producing neurotoxicity in neuron-glia cultures, significant neurotoxicity can be observed when TNF␣ is present in combination with IL-1 and interferon-␥ (Jeohn et al, 1998). Currently, it is not known whether TNF␣, when present with other cytotoxic factors, exerts its effects directly on neurons in neuron-glia cultures or through an indirect mechanism, perhaps through an increased production of microglia-derived proinflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

“…Production of these factors by microglia after exposure to lipopolysaccharide (LPS), the human immunodeficiency virus-1 coat protein gp120, or ␤-amyloid has been well documented (Boje and Arora, 1992;Chao et al, 1992;Dawson et al, 1994;Ii et al, 1996;Kong et al, 1996). Furthermore, activation of microglia and subsequent production of proinflammatory and cytotoxic factors have been attributed to increased neurotoxicity in in vitro neuron-glia cultures treated with LPS, ␤-amyloid, or a combination of IL-1, TNF␣, and interferon-␥ (Chao et al, 1992;Dawson et al, 1994;Jeohn et al, 1998), suggesting that microglia-derived factors such as NO and TNF␣ are important mediators of inflammationmediated neurodegeneration.…”

Section: Abstract: Endotoxin; Lipopolysaccharide; Inflammation; Gliamentioning

confidence: 99%

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Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

et al. 2000

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Inflammation in the brain has been increasingly associated with the development of a number of neurological diseases. The hallmark of neuroinflammation is the activation of microglia, the resident brain immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia nigra of adult rats produced neurodegeneration only in the substantia nigra. Although LPS appeared to impact upon mesencephalic neurons in general, an extensive loss of dopaminergic neurons was observed. Analysis of the abundance of microglia revealed that the substantia nigra had the highest density of microglia. When mixed neuron-glia cultures derived from the rat hippocampus, cortex, or mesencephalon were treated with LPS, mesencephalic cultures became sensitive to LPS at a concentration as low as 10 ng/ml and responded in a dose-dependent manner with the production of inflammatory factors and a loss of dopaminergic and other neurons. In contrast, hippocampal or cortical cultures remained insensitive to LPS treatment at concentrations as high as 10 g/ml. Consistent with in vivo observations, mesencephalic cultures had fourfold to eightfold more microglia than cultures from other regions. The positive correlation between abundance of microglia and sensitivity to LPS-induced neurotoxicity was further supported by the observation that supplementation with enriched microglia derived from mesencephalon or cortex rendered LPS-insensitive cortical neuron-glia cultures sensitive to LPS-induced neurotoxicity. These data indicate that the region-specific differential susceptibility of neurons to LPS is attributable to differences in the number of microglia present within the system and may reflect levels of inflammation-related factors produced by these cells.

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Endotoxin; Lipopolysaccharide; Inflammation; Gliamentioning

confidence: 99%

Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

et al. 2000

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“…TNF-a is known to have potent neurodevelopmental effects by inhibiting neuronal cell survival 11 and cortical dendrite development 12 and synergistic interactions exist between TNF-a and other proinflammatory cytokines in these processes. 12,39 Elevated fetal brain levels of TNF-a have also been implicated in the emergence of enhanced neuronal apoptosis in postnatal life. 17 Furthermore, increased maternal TNF-a levels during pregnancy have been directly associated with a higher incidence of postpubertal psychosis in the offspring.…”

Section: Discussionmentioning

confidence: 99%

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

et al. 2007

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Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced antiinflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro-and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.

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“…Lipopolysaccharide (LPS) is a potent inductor of inflammation and produces the activation of microglia and astrocytes (Lieberman et al, 1989;Benveniste et al, 1990;Chung and Benveniste, 1990) and the induction of diverse cytokines (Lee et al, 1993;Chao et al, 1995;Jeohn et al, 1998). Injection of LPS in the prefrontal cortex (PFC) does not have a similar effect as in SN (Kim et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Pablos¹,

Villarán²,

Argüelles³

et al. 2006

J. Neurosci.

189

176

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Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 g of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-␣; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11␤-[p-(dimethylamino)phenyl]-17␤-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.

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Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures

Cited by 185 publications

References 38 publications

Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

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