Cytotoxicity of cytokines in cerebral microvascular endothelial cell

Kimura, Hitoshi; Gules, Ilker; Meguro, Toshinari; Zhang, Junyi

doi:10.1016/s0006-8993(03)03450-4

Cited by 63 publications

(37 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Treatment with the TNF inhibitor etanercept in a related experimental pathology, LPS induced uveitis, significantly reduced inflammation and apoptosis in the retina (135). These studies support the notion that excessive levels of TNF-alpha contribute to the early events of diabetic retinopathy in particular, because it is a potent inducer of apoptosis in microvascular cells (136,137). Aspirin and other salicylate anti-inflammatory drugs inhibited activation and nuclear translocation of NF-kappaB, expression of inflammatory markers and the loss of microvascular cells, emphasizing the role of inflammation in the early stages of this diabetic complication.…”

Section: Retinopathysupporting

confidence: 61%

Diabetic complications and dysregulated innate immunity

Graves

Kayal²

2008

Front Biosci

225

188

View full text Add to dashboard Cite

Diabetes mellitus is a metabolic disorder that leads to the development of a number of complications. The etiology of each diabetic complication is undoubtedly multifactorial. We will focus on one potential component that may be common in many diabetic complications, dysregulation of innate immunity associated with an increased inflammatory response. High glucose levels lead to shunting through the polyol pathway, an increase in diacylglycerol which activates protein kinase C, an increase in the release of electrons that react with oxygen molecules to form superoxides, and the non-enzymatic glycosylation of proteins that result in greater formation of advanced glycation end products. Each of these can lead to aberrant cell signalling that affects innate immunity for example, by activating the MAP kinase pathway or inducing activation of transcription factors such as NF-kappaB. This may be a common feature of several complications including periodontal disease, atherosclerosis, nephropathy, impaired healing and retinopathy. These complications are frequently associated with increased expression of inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 and enhanced generation of reactive oxygen species. Cause and effect relationship between dysregulation of key components of innate immunity and diabetic complications in many instances have been demonstrated with the use of cytokine blockers and antioxidants.

show abstract

Section: Retinopathysupporting

confidence: 61%

Diabetic complications and dysregulated innate immunity

Graves

Kayal²

2008

Front Biosci

225

188

View full text Add to dashboard Cite

show abstract

“…Few studies have proposed that cytokines might induce endothelial barrier dysfunction via apoptosis (17,(48)(49)(50)(51). However, one report suggests that primary cultures of human BECs are resistant to cell death mediated by TNF-a (18), although this resistance to apoptosis is not observed in primary cultures of BECs of other species (13,48).…”

Section: Discussionmentioning

confidence: 99%

“…TNF receptor 1 (TNFR1) is expressed constitutively on almost every nucleated cell type and tissue, whereas the expression of TNF receptor 2 (TNFR2) is highly regulated with prominent expression in cells of the immune system and endothelium, including BECs (13,14). Increased levels of TNF-a have been reported not only to modulate endothelial TJs and cytoskeleton rearrangement in BECs (15,16) but also to evoke an increase in caspase-3 activation driving BECs into apoptosis (13,17). More recently, a study has proposed that primary cultures of human BECs are resistant to cell death mediated by TNF-a (18).…”

Section: B Lood-brain Barrier (Bbb) Dysfunction Is a Hallmark Of Neurmentioning

confidence: 99%

Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells

Lopez-Ramirez

Fischer

Torres-Badillo

et al. 2012

The Journal of Immunology

110

View full text Add to dashboard Cite

During neuroinflammation, cytokines such as TNF-α and IFN-γ secreted by activated leukocytes and/or CNS resident cells have been shown to alter the phenotype and function of brain endothelial cells (BECs) leading to blood–brain barrier breakdown. In this study, we show that the human BEC line hCMEC/D3 expresses the receptors for TNF-α, TNF receptor 1 and TNF receptor 2, and for IFN-γ. BEC activation with TNF-α alone or in combination with IFN-γ induced endothelial leakage of paracellular tracers. At high cytokine concentrations (10 and 100 ng/ml), this effect was associated with caspase-3/7 activation and apoptotic cell death as evidenced by annexin V staining and DNA fragmentation (TUNEL) assays. In addition, inhibition of JNK and protein kinase C activation at these doses partially prevented activation of caspase-3/7, although only JNK inhibition was partially able to prevent the increase in BEC paracellular permeability induced by cytokines. By contrast, lower cytokine concentrations (1 ng/ml) also led to effector caspase activation, increased paracellular flux, and redistribution of zonula occludens-1 and VE-cadherin but failed to induce apoptosis. Under these conditions, specific caspase-3 and caspase-9, but not caspase-8, inhibitors partially blocked cytokine-induced disruption of tight and adherens junctions and BEC paracellular permeability. Our results suggest that the concentration of cytokines in the CNS endothelial microenvironment determines the extent of caspase-mediated barrier permeability changes, which may be generalized as a result of apoptosis or more subtle as a result of alterations in the organization of junctional complex molecules.

show abstract

“…Other studies have reported that TNF-a is directly toxic to vascular endothelial cells that play a major role in angiogenesis during tumor invasion and metastasis (37). TNF-a induces apoptosis in cultured cerebral endothelial cells through the cleavage of caspase-3 (37).…”

Section: Discussionmentioning

confidence: 99%

Restoration of Tissue Factor Pathway Inhibitor-2 in a Human Glioblastoma Cell Line Triggers Caspase-Mediated Pathway and Apoptosis

George¹,

Gondi²,

Dinh³

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose:The induction of apoptotic pathways in cancer cells offers a novel and potentially useful approach to improve patient responses to conventional chemotherapy. Tissue factor pathway inhibitor-2 (TFPI-2) is a protease inhibitor that is abundant in the extracellular matrix and highly expressed in noninvasive cells but absent or undetectable in highly invasive human glioblastoma cells. Experimental Design: Using a recombinant adeno-associated viral vector carrying human TFPI-2 cDNA, we stably expressed TFPI-2 in U-251 cells, a highly invasive human glioblastoma cell line. Our previous studies showed that restoration of TFPI-2 in glioblastomas effectively prevents cell proliferation, angiogenesis, and tumor invasion. In this study, we determined whether TFPI-2 restoration could induce apoptosis through the caspase-mediated signaling pathway. Results: The results from nuclear chromatin staining, terminal deoxynucleotidyl transferasem ediated dUTP nick end labeling assay, and fluorescence-activated cell sorting analysis showed increased apoptosis in U-251cells after restoration of TFPI-2. Caspase-9 and caspase-3 activity assays showed increased activity, indicating enhanced apoptosis. Immunofluorescence for cleaved caspase-9 and caspase-3 depicted increased expression and colocalization of both molecules.Western blot analysis showed increased transcriptional activities of Fas ligand, tumor necrosis factor-a, Bax, Fas-associated death domain, and tumor necrosis factor receptor 1â ssociated death domain as well as elevated levels of cleaved caspases and poly(ADP-ribose) polymerase. Semiquantitative reverse transcription-PCR depicted increased expression of tumor necrosis factor-a and Fas ligand and the related death domains tumor necrosis factor receptor 1^associated death domain and Fas-associated death domain. Conclusions: Taken together, these results show that restoration of TFPI-2 activates both intrinsic and extrinsic caspase-mediated, proapoptotic signaling pathways and induces apoptosis in U-251 cells. Furthermore, our study suggests that recombinant adeno-associated viral vectorm ediated gene expression offers a novel tool for cancer gene therapy.

show abstract

Cytotoxicity of cytokines in cerebral microvascular endothelial cell

Cited by 63 publications

References 67 publications

Diabetic complications and dysregulated innate immunity

Diabetic complications and dysregulated innate immunity

Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells

Restoration of Tissue Factor Pathway Inhibitor-2 in a Human Glioblastoma Cell Line Triggers Caspase-Mediated Pathway and Apoptosis

Contact Info

Product

Resources

About