A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability

Clauss, Matthias; Sunderkötter, Cord; Sveinbjørnsson, Baldur; Hippenstiel, Stefan; Willuweit, Antje; Marino, Michael W.; Haas, Elvira; Seljelid, Rolf; Scheurich, Peter; Suttorp, N; Grell, Matthias; Risau, Werner

doi:10.1182/blood.v97.5.1321

Cited by 100 publications

(79 citation statements)

References 63 publications

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“…Consistent with this observation, our data showed an association of angiogenesis with MDSC accumulation in tmTNFa-or sTNF-a-expressing tumors. Although tmTNF-a expression has been shown to be upregulated in the tumor endothelium (54) and play an angiogenic role (55), it is possible that tmTNF-a may be a factor in tumor microenvironment that would facilitate MDSCdependent tumor angiogenesis. Briefly, our in vivo data indicated again that tmTNF-a plays an important role in the activation of MDSCs, and thus promotes tumor immune escape, one of the mechanisms involved in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

et al. 2014

The Journal of Immunology

149

144

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It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α–induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α–mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-β, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

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Section: Discussionmentioning

confidence: 99%

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

et al. 2014

The Journal of Immunology

149

144

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“…We have shown recently that expression of tmTNF in endothelial cells leads to the continuous activation of NF-B and the p38/SAPK2, resulting in a constitutive expression of IL-6 and tissue factor in endothelial cells. We could further demonstrate that such activation is permissive for an unrelated cytokine, vascular endothelial growth factor, to act as a permeability-inducing factor (16).…”

mentioning

confidence: 94%

“…Recently, several reports demonstrated that upon appropriate stimulation endothelial cells are, in principle, able to express endogenous TNF, leading to autocrine activation. The TNF mRNA or protein could be detected in HUVEC (13)(14)(15)(16), porcine pulmonary artery endothelial cells (17), and rat brain endothelial cells (18) after stimulation with bacterial cell wall components or proinflammatory cytokines. Evidence for endothelial expression of TNF in vivo is provided by our recent observation that the tumor endothelium of the Meth A fibrosarcoma produces endogenous TNF (16).…”

mentioning

confidence: 99%

“…The TNF mRNA or protein could be detected in HUVEC (13)(14)(15)(16), porcine pulmonary artery endothelial cells (17), and rat brain endothelial cells (18) after stimulation with bacterial cell wall components or proinflammatory cytokines. Evidence for endothelial expression of TNF in vivo is provided by our recent observation that the tumor endothelium of the Meth A fibrosarcoma produces endogenous TNF (16). The hypothesis that endothelial cells may express TNF under pathophysiological conditions is also supported by the detection of TNF-positive endothelial cells in multiple sclerosis lesions (19,20) and in human atheromas (21), although these studies do not distinguish between endothelial cells binding or producing TNF.…”

mentioning

confidence: 99%

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Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

Willuweit

Sass

Schöneberg

et al. 2001

The Journal of Immunology

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Endothelial activation is an important feature of many inflammatory diseases and has been implicated as the cause of vascular complications in disorders such as diabetes, atherosclerosis, and transplant rejection. One of the most potent activators of the endothelium is TNF, which can also be expressed by endothelial cells, causing a permanent, autocrine stimulatory signal. To establish a model of continuous endothelial activation and to elucidate the role of endothelial derived TNF in vivo, we generated transgenic mice expressing a noncleavable transmembrane form of TNF under the control of the endothelial-specific tie2 promoter. Adult tie2-transmembrane TNF-transgenic mice developed chronic inflammatory pathology in kidney and liver, characterized by perivascular infiltration of mononuclear cells into these organs. Along with the infiltrate, an up-regulation of the adhesion molecules ICAM-1 and VCAM-1, but not E-selectin, in the endothelium was observed. Despite predisposition to chronic inflammation these mice were protected from immune-mediated liver injury in a model of Con A-induced acute hepatitis. Although the blood levels of soluble TNF and IFN-γ were increased in transgenic animals after challenge with Con A, no damage of hepatocytes could be detected, as assessed by the lack of increase in plasma transaminase activities and the absence of TUNEL staining in the liver. We conclude that expression of transmembrane TNF in the endothelium causes continuous endothelial activation, leading to both proinflammatory and protective events.

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“…Activation of p38 MAPK is required for expression of and cellular response to vascular endothelial growth factor, which promotes angiogenesis. [80][81][82] Thus, while inactivation of MEKs underlies the pathogenesis of anthrax, their inappropriate activation contributes to the pathogenesis of cancer. This raises the possibility that anthrax LeTx might be used to counter increased levels of MEK activity in tumors.…”

Section: Anthrax and Cancermentioning

confidence: 99%

Anthrax, MEK and Cancer

Bodart¹,

Chopra²,

Liang³

et al. 2002

Cell Cycle

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A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability

Cited by 100 publications

References 63 publications

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

Anthrax, MEK and Cancer

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