Negative regulatory role of PI3‐Kinase in TNF‐induced tumor necrosis

Matschurat, Susanne; Blum, Sabine; Mitnacht-Kraus, Rita; Dijkman, Henry; Kanal, Levent; Waal, R.M.W. de; Clauss, Matthias

doi:10.1002/ijc.11345

Cited by 7 publications

(11 citation statements)

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“…44 In this model, wortmannin increased splenocyte apoptosis, suggesting that decreased cell survival may also contribute to the decreased survival of endotoxemic mice. These in vivo studies, together with our in vitro studies with monocytes and endothelial cells, 15,[22][23][24] strongly suggest that the PI3K pathway suppresses LPS-induced coagulation and inflammation in endotoxemic mice. We predict that inhibition of coagulation would partially reverse the detrimental effects of wortmannin.…”

Section: Discussionsupporting

confidence: 58%

“…wortmannin increases TF expression in endothelial cells. [22][23][24] Endotoxemic mice treated with wortmannin also exhibited enhanced levels of TAT complex in the plasma and increased fibrin deposition in the liver. Taken together, these results indicate that the PI3K-Akt pathway suppresses LPS induction of TF expression in monocytes and limits the activation of the coagulation protease cascade in endotoxemic mice.…”

Section: Discussionmentioning

confidence: 99%

“…16,[22][23][24][25][26][27] The p38MAPK pathway has been shown to play a key role in the LPS induction of inflammatory mediators and coagulation in human and mouse models of endotoxemia. 49 -51 Inhibition of the PI3K-Akt pathway in endotoxemic mice is likely to enhance LPS activation of the p38MAPK pathway and the subsequent expression of pro-inflammatory and procoagulant molecules.…”

Section: Discussionmentioning

confidence: 99%

“…16 Similarly, inhibition of the PI3K-Akt pathway enhanced LPS-induced nitric oxide synthase gene expression in murine peritoneal macrophages and TNF-␣ and vascular endothelial growth factor induction of TF in endothelial cells. 17,[22][23][24] Inhibition of PI3K with wortmannin or LY294002 and expression of dominant-negative Akt increased LPS activation of MAPK pathways and AP-1-dependent transcription. 16 Other studies have shown that phosphorylation of Raf and extracellular signal-regulated kinase (ERK) by Akt inhibits the Raf-MEK-ERK signaling pathway.…”

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confidence: 99%

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PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

Schabbauer

Tencati

Pedersen

et al. 2004

ATVB

221

175

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Objective-In endotoxemia, lipopolysaccharide (LPS) induces a systemic inflammatory response and intravascular coagulation. Monocytes orchestrate the innate immune response to LPS by expressing a variety of pro-inflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣), and the procoagulant molecule, tissue factor (TF). In this study, we analyzed the role of the phosphoinositide 3-kinase (PI3K)-Akt pathway in the activation of coagulation and the innate immune response in a mouse model of endotoxemia. Methods and Results-Wortmannin and LY294002 were used to inhibit the PI3K-Akt pathway. We found that wortmannin inhibited LPS-induced Akt phosphorylation in blood cells. Inhibition of the PI3K-Akt pathway significantly increased TF mRNA expression in blood cells, TF antigen, and thrombin-antithrombin III levels in the plasma, and fibrin deposition in the liver of endotoxemic mice. Inhibition of the PI3K-Akt pathway also strongly enhanced LPS-induced cytokine expression and the levels of soluble E-selectin in the plasma, suggesting enhanced activation of both monocytes and endothelial cells. Wortmannin treatment also increased the number of macrophages in the liver and kidney of endotoxemic mice. Finally, wortmannin and LY294002 dramatically reduced the survival time of endotoxemic mice. Conclusions-These data suggest that the PI3K-Akt pathway suppresses LPS-induced inflammation and coagulation in endotoxemic mice.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

Schabbauer

Tencati

Pedersen

et al. 2004

ATVB

221

175

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“…This, then, can translate into increased expression, stability, nuclear localization, and/or transactivation of the particular immediate early gene. Others (17,23,33,34) have shown that ERK activation by TNF␣ or thrombin can increase Egr-1 and/or TF expression in endothelial cells. Although we observed significant activation of ERK by thrombin and TNF␣, alone or in combination, ablation of the ERK signal had little effect upon the synergistic stimulation of tissue factor expression by TNF␣ plus thrombin.…”

Section: Resultsmentioning

confidence: 99%

Thrombin and Tumor Necrosis Factor α Synergistically Stimulate Tissue Factor Expression in Human Endothelial Cells

Liu

Pelekanakis

Woolkalís

2004

Journal of Biological Chemistry

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Tissue factor is critically important for initiating the activation of coagulation zymogens leading to the generation of thrombin. Quiescent endothelial cells do not express tissue factor on their surface, but many stimuli including cytokines and coagulation proteases can elicit tissue factor synthesis. We challenged human endothelial cells simultaneously with tumor necrosis factor ␣ (TNF␣) and thrombin because many pathophysiological conditions, such as sepsis, diabetes, and coronary artery disease, result in the concurrent presence of circulating inflammatory mediators and activated thrombin. We observed a remarkable synergy in the expression of tissue factor by thrombin plus TNF␣. This was due to altered regulation of the transcription factors c-Jun and c-Fos. The activation of c-Jun was greater and more sustained than that obtained with either thrombin or TNF␣ alone. Thrombin-stimulated expression of c-Fos was both enhanced and prolonged by the concurrent presence of TNF␣. These changes support the increased availability of c-Jun/c-Fos AP-1 complexes for mediating transcription at the tissue factor promoter. Transcription factors downstream of the extracellular signal-regulated kinases as well as changes in NFB regulation were not involved in the synergistic increase in tissue factor expression by thrombin and TNF␣. Thus, concurrent exposure of vascular endothelial cells to cytokines and procoagulant proteases such as thrombin can result in greatly enhanced tissue factor expression on the endothelium, thereby perpetuating the prothrombotic phenotype of the endothelium.Many diseases with a pronounced inflammatory component, such as sepsis, type II diabetes, coronary artery disease, heparin-induced thrombocytopenia, and anti-phospholipid syndrome, also exhibit enhanced activation of coagulation enzymes (1-5). These serine proteases, most notably thrombin, stimulate protease-activated receptors (PARs) 1 on the surface of endothelial cells. Signaling through the PARs shifts the endothelium toward a prothrombotic phenotype, exacerbating the initiating pathophysiological condition. Our interest in thrombin signaling by endothelial cells (6, 7) led us to question how inflammatory mediators such as TNF␣ might alter thrombininitiated signaling events and thereby bolster the prothrombotic phenotype of the endothelium. Normally, the apical surface of endothelial cells is designed to minimize interactions with circulating coagulation zymogens and blood cells. Inflammatory stimuli (cytokines, lipopolysaccharide, vascular endothelial cell growth factor, sphingosine 1-phosphate, thrombin (8 -12)) can alter the anticoagulatory phenotype of the endothelium by promoting the expression of adhesive molecules, receptors, and chemoattractants. Expression of tissue factor (TF), the coagulation Factor VII receptor, on the surface of endothelial cells serves as an excellent marker for an activated endothelium with an inflamed and procoagulant phenotype (13,14). Binding of Factor VII to tissue factor can then initiate the consecutive...

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The role of tissue factor isoforms in cancer biology

Leppert

Eisenreich

2014

Int. J. Cancer

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Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic-and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology.Tissue factor (TF) is a glycoprotein and an evolutionary conserved member of the Class II cytokine receptor family, which was found in different species, such as human, mouse, rat, fish as well as in Drosophila melanogaster and mosquitos. 1-3 TF is expressed in two natural occurring protein isoforms, full-length (fl)TF and alternatively spliced (as)TF. [4][5][6] In human, flTF consists of a short intracellular domain (21 amino acids), a transmembrane domain (23 amino acids) and an extracellular domain (219 amino acids). 7 flTF is anchored to the cell membrane. 7,8 The primary function of flTF is the initiation of the blood coagulation cascade. 2,7,8 Beside this, flTF plays an important role in a variety of other biological processes, such as protease-activated receptor (PAR-)2-mediated cell signaling and tumor progression. 2,9,10 Due to alternative splicing the fifth exon of the primary TF transcript is excluded. 5,7 Translation of this messenger (m)RNA splice variant leads to the generation of asTF on protein level. asTF lacks the transmembrane domain and is therefore soluble. 7 Compared with flTF, asTF exhibits low prothrombogenic potential. 4,7,8 However, this isoform was recently linked more closely to angiogenesis, survival and cell growth. 3,[11][12][13][14] Post-transcriptional expression control regulate a variety of biologic functions, such as tumor cell invasion, metastasis and angiogenesis in cancer as well as in other settings. [15][16][17][18] Two major mechanisms modulate post-transcriptional expression: micro (mi)RNAs and alternative splicing processes. 16 In this review, we will discuss the latest findings regarding the impact of TF and its isoforms on cancer biology with special focus on pathophysiologic-relevant functions, such as thrombogenicity, tumor cell growth and angiogenesis. Moreover, we will shed light on the mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Cancer-Related Stimulation of TF ExpressionSeveral stimuli, such as hypoxia, vascular endothelial growth factor (VEGF) and the proinflammatory cytokine tumor necrosis fact...

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Negative regulatory role of PI3‐Kinase in TNF‐induced tumor necrosis

Cited by 7 publications

References 46 publications

PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

Thrombin and Tumor Necrosis Factor α Synergistically Stimulate Tissue Factor Expression in Human Endothelial Cells

The role of tissue factor isoforms in cancer biology

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