Lipopolysaccharide stimulation of ERK1/2 increases TNF-α production via Egr-1

2002 ◽  
Vol 282 (6) ◽  
pp. C1205-C1211 ◽  
Author(s):  
Liang Shi ◽  
Raj Kishore ◽  
Megan R. McMullen ◽  
Laura E. Nagy
Keyword(s):  
Dominant Negative ◽  
Protein Accumulation ◽  
Extracellular Signal Regulated Kinase ◽  
Early Growth Response ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

Lipopolysaccharide (LPS) is a potent activator of tumor necrosis factor-α (TNF-α) production by macrophages. LPS stimulates the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and increases TNF-α mRNA and protein accumulation in RAW 264.7 murine macrophages. However, the role of ERK1/2 activation in mediating LPS-stimulated TNF-α production is not well understood. Inhibition of ERK1/2 activation with PD-98059 or overexpression of dominant negative ERK1/2 decreased LPS-induced TNF-α mRNA quantity. LPS rapidly increased early growth response factor (Egr)-1 binding to the TNF-α promoter; this response was blunted in cells treated with PD-98059 or transfected with dominant-negative ERK1/2. Using a chloramphenicol acetyltransferase reporter gene linked to the Egr-1 promoter, we show that LPS increased Egr-1 promoter activity via an ERK1/2-dependent mechanism. These results delineate the role of ERK1/2 activation of Egr-1 activity in mediating LPS-induced increases in TNF-α mRNA expression in macrophages.

Modulation of the Activation of Extracellular Signal-Regulated Kinase (ERK) and the Production of Inflammatory Mediators by ADP-Ribosylation Inhibitors

2003 ◽  
Vol 384 (10-11) ◽  
pp. 1509-1513 ◽  
Author(s):  
C. Le Page ◽  
J. Wietzerbin
Keyword(s):  
Inflammatory Mediators ◽  
Nuclear Factor Κb ◽  
Oxygen Species ◽  
Extracellular Signal Regulated Kinase ◽  
Adp Ribosylation ◽  
Raw264.7 Macrophages ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract ADP-ribosylation is involved in nuclear factor κB (NF-κB)-dependent gene expression induced by lipopolysaccharide in murine macrophages. Here we have investigated the mechanism by which ADP-ribosylation inhibitors block signaling pathways induced in macrophages. In RAW264.7 macrophages the inducers of NF-κB activate the production of reactive oxygen species and three mitogenactivated protein kinases (MAPK), the extracellular signal regulated kinase (ERK), the c-jun N-terminal kinase/stress-activated protein kinase (JNK), and p38. We demonstrate that ADP-ribosylation inhibitors specifically inhibit ERK MAPK activation and reduce the release of inflammatory mediators such as tumor necrosis factor α (TNF-α), IL-6 and nitrite.

The Role of Tumor Necrosis Factor-α (TNF-α) Polymorphisms in Gastric Cancer: a Meta-Analysis

2021 ◽  
Author(s):  
Maryam Gholamalizadeh ◽  
Samaneh Mirzaei Dahka ◽  
Hadi Sedigh Ebrahim-Saraie ◽  
Mohammad Esmail Akbari ◽  
Azam Pourtaheri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Meta Analysis ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption

2001 ◽  
Vol 281 (4) ◽  
pp. G890-G898 ◽  
Author(s):  
Suzana D. Savkovic ◽  
Akila Ramaswamy ◽  
Athanasia Koutsouris ◽  
Gail Hecht
Keyword(s):  
Tight Junction ◽  
Signaling Cascades ◽  
Extracellular Signal Regulated Kinase ◽  
Intestinal Epithelia ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Functional Consequences ◽  
First Time ◽  
Necrosis Factor ◽  
Iκbα Degradation

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear factor (NF)-κB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation and to determine whether these pathways parallel or diverge from those that alter permeability. EPEC-induced phosphorylation and degradation of the primary inhibitor of NF-κB (IκBα) were tumor necrosis factor (TNF)-α and interleukin (IL)-1β independent. In contrast to Salmonella typhimurium, EPEC-stimulated IκBα degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK)-1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated IκBα degradation and IL-8 expression. Although ERK1/2 can activate MLCK, its inhibition had no impact on EPEC disruption of the tight junction barrier. In conclusion, EPEC-induced inflammation 1) is TNF-α and IL-1β receptor independent, 2) utilizes pathways differently from S. typhimurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated signaling cascades have been linked to independent functional consequences.

Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α

2002 ◽  
Vol 282 (2) ◽  
pp. G257-G266 ◽  
Author(s):  
Hailing Liu ◽  
Brett E. Jones ◽  
Cynthia Bradham ◽  
Mark J. Czaja
Keyword(s):  
Cell Death ◽  
Oxidant Stress ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Tnf Α ◽  
Cyp2e1 Expression ◽  
Factor Α ◽  
Jnk Activation ◽  
Cytochrome P 450 ◽  
Necrosis Factor

The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-α (TNF-α)-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-α death. TNF-α treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-α response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-κB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-α-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-α stimulation. Sensitization to TNF-α-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-α toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-α toxicity in liver disease.

Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding

1999 ◽  
Vol 112 (21) ◽  
pp. 3603-3617 ◽  
Author(s):  
J. Schlondorff ◽  
C.P. Blobel
Keyword(s):  
Tumor Necrosis ◽  
Ectodomain Shedding ◽  
Membrane Glycoproteins ◽  
Tnf Α ◽  
Disintegrin Domain ◽  
Protein Ectodomain Shedding ◽  
Integrin Ligands ◽  
Factor Α ◽  
Necrosis Factor

Metalloprotease-disintegrins (ADAMs) have captured our attention as key players in fertilization and in the processing of the ectodomains of proteins such as tumor necrosis factor (α) (TNF(α)), and because of their roles in Notch-mediated signaling, neurogenesis and muscle fusion. ADAMs are integral membrane glycoproteins that contain a disintegrin domain, which is related to snake-venom integrin ligands, and a metalloprotease domain (which can contain or lack a catalytic site). Here, we review and critically discuss current topics in the ADAMs field, including the central role of fertilin in fertilization, the role of the TNF(α) convertase in protein ectodomain processing, the role of Kuzbanian in Notch signaling, and links between ADAMs and processing of the amyloid-precursor protein.

scholarly journals Heat shock and tumor necrosis factor-α induce apoptosis in bovine preimplantation embryos through a caspase-9-dependent mechanism

Reproduction ◽  
2007 ◽  
Vol 133 (6) ◽  
pp. 1129-1137 ◽  
Author(s):  
Bárbara Loureiro ◽  
Amber Mary Brad ◽  
Peter James Hansen
Keyword(s):  
Heat Shock ◽  
Tumor Necrosis ◽  
Preimplantation Embryos ◽  
Caspase 8 ◽  
Mitochondrial Depolarization ◽  
Caspase 9 ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

Heat shock and tumor necrosis factor-α (TNF-α) induce apoptosis through different mechanisms, with heat shock acting to cause mitochondrial depolarization and caspase-9 activation, while TNF-α acts through a receptor-mediated process to activate caspase-8. In some cells, however, TNF-α can also cause mitochondrial depolarization and caspase-9 activation. In the present study, we tested the hypothesis that heat shock at 41 °C and TNF-α induce apoptosis in bovine preimplantation embryos through a caspase-9-dependent mechanism. Treatment of embryos with either heat shock (41 °C) or TNF-α increased the proportion of blastomeres that were TUNEL positive and the proportion of embryos exhibiting elevated caspase-9 activity. Furthermore, the caspase-9 inhibitor, z-LEHD-fmk, blocked the increase in TUNEL-positive nuclei caused by both heat shock and TNF-α. For embryos at day 6 after insemination, for example, the percent of blastomeres positive for TUNEL was 3.6% for control embryos, 11.1% for embryos cultured at 41 °C, and 15.1% for embryos cultured with 10 ng/ml TNF-α. In the presence of z-LEHD-fmk, the percent of cells positive for TUNEL was 3.7% for control embryos, 6.1% for embryos cultured at 41 °C, and 8% for embryos cultured with 10 ng/ml TNF-α. Although TNF-α did not cause a measurable increase in caspase-8 activity, there was a tendency (P= 0.07) for treatment of embryos with z-IETD-fmk, an inhibitor of caspase-8, to partly reduce the magnitude of the increase in TUNEL-positive cells caused by TNF-α. The percent of cells that were TUNEL positive was increased by TNF-α from 9.7 to 19.7% in the absence of inhibitor and from 13.0 to 15.6% in the presence of z-IETD-fmk. Results indicate that induction of apoptosis by both heat shock and TNF-α involve activation of caspase-9-dependent pathways. It is likely that TNF-α also activates apoptotic pathways involving caspase-8 but that the degree of activation is small and caspase-9-dependent pathways are required for full activation of apoptosis.

Association Between Tumor Necrosis Factor-α Gene Polymorphism and Sasang Constitution in Cerebral Infarction

2005 ◽  
Vol 33 (04) ◽  
pp. 547-557 ◽  
Author(s):  
Jae-Young Um ◽  
Jae-Heung Lee ◽  
Jong-Cheon Joo ◽  
Kyung-Yo Kim ◽  
Eun-Hee Lee ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cerebral Infarction ◽  
Promoter Region ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Sasang Constitution ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

During the last decade, a growing corpus of evidence has indicated an important role of cytokines in the development of brain damage following cerebral ischemia. Tumor necrosis factor-α (TNF-α), a potent immunomodulator and pro-inflammatory cytokine, has been implicated in many pathological processes. In this study, we examined whether promoter region polymorphism in the TNF-α gene at position –308 affects the odds of cerebral infarction (CI) and whether genetic risk is enhanced by Sasang constitutional classification. Two hundred and twelve CI patients and 610 healthy controls were genotyped and determined according to Sasang constitutional classification. A significant decrease was found for the TNF-α A allele in CI patients compared with controls ( p = 0.033, odds ratio, OR: 0.622). However, there was no significant association between TNF-α polymorphism and Sasang constitution in CI patients. Our finding suggests that TNF-α promoter region polymorphism is responsible for susceptibility to CI in Koreans.

scholarly journals Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular β-epithelial Na+ channel

2020 ◽  
Vol 318 (4) ◽  
pp. H1018-H1027 ◽  
Author(s):  
Jeremy W. Duncan ◽  
Subhi Talal Younes ◽  
Emily Hildebrandt ◽  
Michael J. Ryan ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Function ◽  
Mapk Signaling ◽  
Pregnant Rats ◽  
Tnf Α ◽  
Factor Α ◽  
Placental Ischemia ◽  
Necrosis Factor

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of β-epithelial Na+ channel (βENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, βENaC is an essential signaling element in transduction of pressure-induced (aka “myogenic”) constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular βENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular βENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of βENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell βENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1–100 ng/mL) for 16–24 h. TNF-α reduced βENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated βENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced βENaC-mediated vascular function. NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular β-epithelial sodium channel (βENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced βENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.

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