Second Messenger Systems in the Regulation of Cytokines and Adhesion Molecules in the Central Nervous System

Benveniste, Etty N.; Huneycutt, Brandon S.; Shrikant, Protul; Ballestas, Mary E.

doi:10.1006/brbi.1995.1029

Cited by 32 publications

(12 citation statements)

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“…The activation of inflammatory responses in brain is normally under tight regulation that prevents the accumulation of potentially cytotoxic mediators including cytokines and reactive oxygen species (1)(2)(3). It has therefore been suggested that intrinsic mechanisms exist that maintain the brain in a refractory state of inflammatory activation.…”

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confidence: 99%

“…It has therefore been suggested that intrinsic mechanisms exist that maintain the brain in a refractory state of inflammatory activation. In primary cultures of rat astrocytes, we showed that neurotransmitter norepinephrine (NE) 1 prevents induction of the inducible form of nitric oxide synthase (NOS2) (4,5) by bacterial endotoxin lipopolysaccharide (LPS) or by a combination of proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interferon ␥). Similarly, others show that NE reduces glial expression of pro-inflammatory cytokines including interleukin 1␤ and tumor necrosis factor ␣ (6 -9) and of cell adhesion molecules (13).…”

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confidence: 99%

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Norepinephrine Increases IκBα Expression in Astrocytes

Gavrilyuk¹,

Russo²,

Heneka³

et al. 2002

Journal of Biological Chemistry

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The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory IB␣ protein accompanied by an increase in steady state levels of IB␣ mRNA. Maximal increases were observed at 30 -60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to ␤-adrenergic receptors. NE activated a 1.3-kilobase IB␣ promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a ␤-antagonist and by protein kinase A inhibitors but not by an NFB inhibitor. NE increased IB␣ protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of IB␣. IB␣ was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain IB␣ levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that IB␣ expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.The activation of inflammatory responses in brain is normally under tight regulation that prevents the accumulation of potentially cytotoxic mediators including cytokines and reactive oxygen species (1-3). It has therefore been suggested that intrinsic mechanisms exist that maintain the brain in a refractory state of inflammatory activation. In primary cultures of rat astrocytes, we showed that neurotransmitter norepinephrine (NE) 1 prevents induction of the inducible form of nitric oxide synthase (NOS2) (4, 5) by bacterial endotoxin lipopolysaccharide (LPS) or by a combination of proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interferon ␥). Similarly, others show that NE reduces glial expression of pro-inflammatory cytokines including interleukin 1␤ and tumor necrosis factor ␣ (6 -9) and of cell adhesion molecules (13). A similar role for NE in regulating inflammatory events in brain is supported by our recent findings that experimental depletion of brain NE levels by chemical lesion of the locus ceruleus (LC) increases the cortical inflammatory responses to injection of aggregated amyloid ␤ (14). The fact that LC neurons are lost in Alzheimer's disease (15) and that levels of ␤ 2 -adrenergic receptor (␤ARs) are reduced in astrocytes in multiple sclerosis patients (16,17) suggests that diminished NE levels or perturbations of the NE-signaling system contribute to the neuroinflammation that occurs in these diseases.The mechanism(s) by which NE reduces inflammatory gene expression is not yet well defined. In astrocytes, we found that NE induced protein binding to a 27-bp region of the rat NOS2 promoter, which is located immediately upstream of a NFB binding site located at bp position Ϫ107 to Ϫ96 (18). This 27-bp region contains several potenti...

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confidence: 99%

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confidence: 99%

Norepinephrine Increases IκBα Expression in Astrocytes

Gavrilyuk¹,

Russo²,

Heneka³

et al. 2002

Journal of Biological Chemistry

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“…The increase in fak mRNA and protein levels with microglial activation further supports the importance of this signaling pathway in microglia. JAKs participate in numerous cytokine signaling pathways (Benveniste et al, 1995;Ernst et al, 1996;Liva et al, 1999;Ernst et al, 1999). JAK2 interacts with the GM-CSF receptor in microglia suggesting that it promotes proliferation (Liva et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of protein tyrosine kinase genes during microglial activation

Krady

Basu

Levison

et al. 2002

Glia

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Protein tyrosine kinase (PTK) activity is abundant in microglia, but the PTKs that participate in their activation have not been identified. For these studies, we used three paradigms to characterize PTK expression during microglial activation: resting and activated microglia were bulk fractionated from the adult brain, cultured newborn microglia were treated with lipopolysaccharide (LPS) to model the transition from activated toward phagocytic microglia, and PTK expression was examined in activated microglia in situ after facial nerve axotomy. Two PCR-based strategies were used to show that 21 different PTK genes are expressed by rat brain microglia: 5 receptor PTKs, 10 nonreceptor PTKs, and 6 members of the src family. Seven of the 21 PTKs were examined in greater detail. Five PTK mRNAs (fgr, hck, fak, jak-2, and flk-1) increased expression across all three models of activation. We conclude that they represent key components in the cascades that participate in microglial activation. In contrast, expression of fes and fms correlated with stimuli that affect microglial proliferation. Four of the PTKs (hck, fgr, fes, and fms) are believed to be myeloid cell specific and were not expressed by cultured astrocytes. HCK and FAK protein were also not expressed in lysates of immature astrocytes and oligodendrocytes. Because of their putative specificity, these kinases represent potential targets for inhibitors of microglial activation. Because reactive microglia can exacerbate the severity of neurological diseases, the identification of specific kinases that participate in microglial activation represents an important advance toward the development of new therapeutics.

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“…Nerve growth factor (NGF), neurotrophin-3 (NT-3), interleukin (IL)-1, IL-6, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor-· (TNF-·) have been reported to be released by microglia [37][38][39][40][41]. Recently, we have also detected the temporal gene expression of inflammatory cytokines including TNF-·, IL-1, IL-6, transforming growth factor-ß (TGF-ß) and inducible nitric oxide synthase (iNOS) in activated microglia in vitro [unpubl.…”

Section: Proliferation Of Ameboid Microglia In Situmentioning

confidence: 99%

Regulatory Factors and Functions of Microglia during Development

Dheen¹,

Hao²,

Ng³

et al. 2002

Neuroembryol Aging

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This article reviews current knowledge on the origin and development of microglia as well as on regulatory factors that influence microglial development within the neural tube during embryogenesis. Ameboid microglia found in the developing neural tube originate from mesodermal precursors derived from the yolk sac. These microglial cells, which exhibit characteristic features of reactive microglia, undergo mitosis in situ in the nervous parenchyma and function as the full-blown phagocytes involved in the removal of cellular debris resulting from neural tube defect or normal cellular turnover. During embryogenesis, the microglia express various cytokines, growth factors and chemokines. Some of those factors together with other local factors may influence the proliferation and activation of microglia in the developing neural tube.

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Second Messenger Systems in the Regulation of Cytokines and Adhesion Molecules in the Central Nervous System

Cited by 32 publications

References 0 publications

Norepinephrine Increases IκBα Expression in Astrocytes

Norepinephrine Increases IκBα Expression in Astrocytes

Differential expression of protein tyrosine kinase genes during microglial activation

Regulatory Factors and Functions of Microglia during Development

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