scholarly journals The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Rui Chen ◽  
Guofang Xue ◽  
Christian Hölscher
Keyword(s):  
Cytokine Production ◽  
Glutamate Release ◽  
Synaptic Function ◽  
Aminobutyric Acid ◽  
Neuron Activity ◽  
Common Disease ◽  
The Central Nervous System ◽  
Factor Α ◽  
Necrosis Factor

AbstractEpilepsy is a common disease  in the central nervous system. There is growing evidence that epilepsy is associated with glial cells, including astrocytes. Tumor necrosis factor α (TNFα) is a “master regulator” of proinflammatory cytokine production and is secreted by microglia and astrocytes. TNFα secreted by microglia can activate astrocytes. Additionally, TNFα can regulate neuron activity and induce epilepsy by increasing the glutamate release, reducing the expression of γ-aminobutyric acid, inducing neuroinflammation and affecting the synaptic function in astrocytes. This review summarizes the signaling pathways and receptors of TNFα acting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.

Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction

1999 ◽  
Vol 277 (5) ◽  
pp. L1057-L1065 ◽  
Author(s):  
Mir H. Ali ◽  
Scott A. Schlidt ◽  
Navdeep S. Chandel ◽  
Karen L. Hynes ◽  
Paul T. Schumacker ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Umbilical Vein ◽  
Endothelial Permeability ◽  
Ros Generation ◽  
Transendothelial Electrical Resistance ◽  
Tnf Α ◽  
Factor Α ◽  
Induced Changes ◽  
Necrosis Factor

Prolonged hypoxia produces reversible changes in endothelial permeability, but the mechanisms involved are not fully known. Previous studies have implicated reactive oxygen species (ROS) and cytokines in the regulation of permeability. We tested whether prolonged hypoxia alters permeability to increasing ROS generation, which amplifies cytokine production. Human umbilical vein endothelial cell (HUVEC) monolayers were exposed to hypoxia while secretion of tumor necrosis factor-α (TNF-α), interleukin (IL)-1α, IL-6, and IL-8 was measured. IL-6 and IL-8 secretion increased fourfold over 24 h in a pattern corresponding to changes in HUVEC permeability measured by transendothelial electrical resistance (TEER). Addition of exogenous IL-6 to normoxic HUVEC monolayers caused time-dependent changes in TEER that mimicked the hypoxic response. An antibody to IL-6 significantly attenuated the hypoxia-induced changes in TEER (86 ± 4 vs. 63 ± 3% with hypoxia alone at 18 h), whereas treatment with anti-IL-8 had no effect. To determine the role of hypoxia-induced ROS on this response, HUVEC monolayers were incubated with the antioxidants ebselen (50 μM) and N-acetyl-l-cysteine (NAC, 1 mM) before hypoxia. Antioxidants attenuated hypoxia-induced IL-6 secretion (13 ± 2 pg/ml with ebselen and 19 ± 3 pg/ml with NAC vs. 140 ± 15 pg/ml with hypoxia). Ebselen and NAC prevented changes in TEER during hypoxia (94 ± 2% with ebselen and 90 ± 6% with NAC vs. 63 ± 3% with hypoxia at 18 h). N-nitro-l-arginine (500 μM) did not decrease hypoxia-induced changes in dichlorofluorescin fluorescence, IL-6 secretion, or TEER. Thus ROS generated during hypoxia act as signaling elements, regulating secretion of the proinflammatory cytokines that lead to alterations of endothelial permeability.

Distinct pathways of LPS-induced NF-κB activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2229-2237 ◽  
Author(s):  
Evangelos Andreakos ◽  
Sandra M. Sacre ◽  
Clive Smith ◽  
Anna Lundberg ◽  
Serafim Kiriakidis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
Myeloid Differentiation ◽  
Iκb Kinase ◽  
Factor Α ◽  
First Time ◽  
Lps Signaling ◽  
Necrosis Factor

Abstract How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)–κB and inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced IκBα phosphorylation, NF-κB activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor IκB kinase 2 (IKK2) are required for NF-κB activation or tumor necrosis factor α (TNFα), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon β (IFNβ). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-κB activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected.

scholarly journals The role of cytokines in modulating learning and memory and brain plasticity

2020 ◽  
Vol 4 ◽  
pp. 239821282097980
Author(s):  
Julie-Myrtille Bourgognon ◽  
Jonathan Cavanagh
Keyword(s):  
Learning And Memory ◽  
Brain Plasticity ◽  
Homeostatic Plasticity ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Factor Α ◽  
Peripheral Immune Cells ◽  
Necrosis Factor

Cytokines are proteins secreted in the central nervous system by neurons, microglia, astrocytes and infiltrating peripheral immune cells under physiological and pathological conditions. Over the last 20 years, a growing number of reports have investigated the effects of these molecules on brain plasticity. In this review, we describe how the key cytokines interleukin 1β, interleukin 6 and tumour necrosis factor α were found to support long-term plasticity and learning and memory processes in physiological conditions. In contrast, during inflammation where cytokines levels are elevated such as in models of brain injury or infection, depression or neurodegeneration, the effects of cytokines are mostly detrimental to memory mechanisms, associated behaviours and homeostatic plasticity.

Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells

2012 ◽  
Vol 71 (5) ◽  
pp. 768-776 ◽  
Author(s):  
Arnaud Hot ◽  
Vanina Lenief ◽  
Pierre Miossec
Keyword(s):  
Platelet Aggregation ◽  
Migration And Invasion ◽  
Human Endothelial Cells ◽  
Qrt Pcr ◽  
Functional Assays ◽  
Affymetrix Microarrays ◽  
Stromal Cell Derived Factor ◽  
Factor Α ◽  
Necrosis Factor

ObjectiveCardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor α (TNFα) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction.MethodsPrimary human EC were treated with IL-17 alone or combined with TNFα. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion.ResultsIL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFα. IL-17 plus TNFα induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL-6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFα. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state.ConclusionThese results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.

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