Superoxide responses of endothelial cells to C5a and TNF-alpha: divergent signal transduction pathways

1992 ◽  
Vol 263 (1) ◽  
pp. L51-L59 ◽  
Author(s):  
H. S. Murphy ◽  
J. A. Shayman ◽  
G. O. Till ◽  
M. Mahrougui ◽  
C. B. Owens ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Cell Monolayers ◽  
Kinase C ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

There is increasing evidence that endothelial cells respond to a variety of mediators. In the current studies rat pulmonary artery endothelial cells (RPAEC) responded to human recombinant C5a and tumor necrosis factor-alpha (TNF-alpha) with the generation of superoxide (O2-). RPAEC responsiveness was dependent on whether cells had been obtained from confluent or subconfluent cell monolayers. RPAEC responded to C5a and TNF-alpha in a dose-dependent manner, with increases in intracellular Ca2+ (Cai2+), formation of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], and generation of O2-. Optimal O2- responses occurred in cells that had been pretreated with the inhibitor of superoxide dismutase (SOD), diethyldithiocarbamate, and O2- responses were allopurinol insensitive. Pertussis toxin pretreatment abolished the ability of C5a to cause increases in Ins(1,4,5)P3 and Cai2+ and formation of O2- but did not inhibit the changes in Cai2+ and formation of O2- after addition of TNF-alpha. The O2- response to C5a but not to TNF-alpha was abolished by pretreatment with the inhibitor of protein kinase C, staurosporine. These data indicate that signal transduction events in response to C5a and TNF-alpha were fundamentally different.

scholarly journals Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

2004 ◽  
Vol 11 (6) ◽  
pp. 1140-1147 ◽  
Author(s):  
Hidenori Matsuzaki ◽  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyoshi Wakahara ◽  
Toshiharu Kondo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

scholarly journals Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2578-2590
Author(s):  
EM Paleolog ◽  
SA Delasalle ◽  
WA Buurman ◽  
M Feldmann
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tissue Factor ◽  
Adhesion Molecules ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Cell Responses ◽  
Factor Alpha ◽  
Necrosis Factor

Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion molecules, enhances cytokine production, and induces tissue factor procoagulant activity. In the present study, we have examined the relative roles of the two cell surface receptors for TNF- alpha (p55 and p75) on endothelial cells, using antibodies with both agonistic and antagonistic activities. We report that anti-p55 receptor agonistic antibody Htr-9 induces the expression of tissue factor antigen and the release of interleukin-8 (IL-8) and granulocyte- macrophage colony-stimulating factor (GM-CSF). In contrast, there is very little or no activation of endothelial cell responses by an anti- p75 agonist. TNF-alpha-induced expression of tissue factor and adhesion molecules, and release of IL-8 and GM-CSF, are decreased by antibodies with antagonistic activities for either receptor, although the effect of anti-p55 antibodies is markedly greater than that of anti-p75 antibodies. The responses of endothelial cells to lymphotoxin/TNF-beta are significantly decreased by anti-p55 antagonists alone. Our data suggest that endothelial cell responses to TNF-alpha, such as expression of tissue factor and adhesion molecules for mononuclear cells, which may be important in the pathogenesis of atherosclerosis, are mediated predominantly, but not exclusively, by the p55 TNF receptor.

scholarly journals Tumor necrosis factor-alpha modulation of glycoprotein Ib alpha expression in human endothelial and erythroleukemia cells

Blood ◽  
1992 ◽  
Vol 80 (1) ◽  
pp. 153-161 ◽  
Author(s):  
V Rajagopalan ◽  
DW Essex ◽  
SS Shapiro ◽  
BA Konkle
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Protein Expression ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mrna Level ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract Glycoprotein Ib alpha (GpIb alpha) is a platelet membrane Gp that binds von Willebrand factor and mediates platelet adhesion to subendothelium. We have found both GpIb alpha mRNA and protein in human umbilical vein endothelial cells (HUVEC). In previously published work we reported that combined treatment with interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) markedly increased the GpIb alpha mRNA level in HUVEC. We have now documented that TNF-alpha alone induces GpIb alpha mRNA and protein expression, studied the kinetics of this response, and investigated potential mechanisms of the TNF-alpha effect. GpIb alpha mRNA induction by TNF-alpha is detectable as early as 2 hours after exposure to this cytokine, and reaches a maximal level after 20 to 24 hours. Using a nuclear run-on assay we found that GpIb alpha gene transcription is increased approximately 10-fold after 2 hours of TNF-alpha treatment. Furthermore, using two monoclonal antibodies that recognize different epitopes of GpIb alpha, we found that the protein expression in endothelial cells is markedly increased by TNF-alpha. Interleukin-1 (IL-1) and the phorbol ester phorbol myristate acetate, which mimic many effects of TNF-alpha on endothelial cells, have no effect on endothelial or human erytholeukemia (HEL)-cell GpIb alpha mRNA. TNF-alpha treatment for 24 hours increases the HEL cell GpIb alpha mRNA level approximately fourfold, showing a time- and dose-dependent effect similar to that seen in HUVEC. TNF-alpha-induced GpIb alpha mRNA and protein synthesis may play a role in mediating platelet or other cell interaction with activated endothelium. Unlike other endothelial pro-thrombotic and pro-adhesive proteins induced by TNF-alpha, GpIb alpha is not induced by IL-1 treatment, which suggests a novel pathway for induction of this protein.

scholarly journals The receptor for interleukin 3 is selectively induced in human endothelial cells by tumor necrosis factor alpha and potentiates interleukin 8 secretion and neutrophil transmigration

1993 ◽  
Vol 90 (23) ◽  
pp. 11137-11141 ◽  
Author(s):  
E I Korpelainen ◽  
J R Gamble ◽  
W B Smith ◽  
G J Goodall ◽  
S Qiyu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Scatchard Analysis ◽  
Necrosis Factor Alpha ◽  
High Affinity ◽  
Factor Alpha ◽  
Necrosis Factor

Interleukin (IL)-3 stimulates hemopoiesis in vitro. However, IL-3 is not normally found in bone marrow, raising doubts as to the in vivo role of IL-3. We have found that human umbilical vein endothelial cells (HUVEC) express functional high-affinity receptors for IL-3 after stimulation with tumor necrosis factor alpha (TNF-alpha), IL-1 beta, or lipopolysaccharide, and that this receptor is involved in inflammatory phenomena. TNF-alpha caused time- and dose-dependent up-regulation of mRNA for the IL-3 receptor alpha and beta chains, with maximal effects occurring 16-36 h after stimulation with TNF-alpha at 100 units/ml. Induction of mRNA correlated with protein expression on the cell surface as judged by monoclonal antibody staining and by the ability of HUVEC to specifically bind 125I-labeled IL-3. Scatchard analysis under optimal conditions of TNF-alpha stimulation revealed approximately 1500 IL-3 receptors per cell, which were of a high-affinity class (Kd = 500 pM) only. In contrast to a previous report, receptors for granulocyte-macrophage colony-stimulating factor could not be detected. IL-3 binding to TNF-alpha-activated HUVEC enhanced IL-8 production, E-selection expression, and neutrophil transmigration. The selective induction of a functional IL-3 receptor on endothelial cells suggests that, beyond hemopoiesis, IL-3 may have an important role in chronic inflammation and in allergic diseases.

scholarly journals Opposite effects of tumor necrosis factor alpha on the sphingomyelin- ceramide pathway in two myeloid leukemia cell lines: role of transverse sphingomyelin distribution in the plasma membrane

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1465-1472 ◽  
Author(s):  
A Bettaieb ◽  
M Record ◽  
MG Come ◽  
AC Bras ◽  
H Chap ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Dependent Cell ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Ceramide Generation ◽  
Dose Dependent ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF alpha) mediates proliferation, functional activation, and apoptotic cell death depending on the target cell type. Although sphingomyelin (SPM) hydrolysis and ceramide generation may function as an important mediator in TNF alpha signaling, the molecular mechanisms of the signaling pathway(s) are still not well understood. The aim of the present study is to compare the effect of TNF alpha on SPM metabolism and cell growth in two myeloid leukemic cell lines (U937 and KG1a) that differ in their sensitivity to TNF alpha. Our results show that TNF alpha induced apoptosis in U937 but not in KG1a cells. TNF alpha triggered in KG1a cells neither SPM hydrolysis nor ceramide generation, but induced SPM synthesis and ceramide breakdown as well as dose-dependent cell proliferation. In contrast, TNF alpha induced in U937 SPM hydrolysis and ceramide generation as well as dose-dependent cell death. Synthetic cell permeant ceramide, as well as natural ceramide, generated by treatment with bacterial sphingomyelinase (SPMase), all induced apoptosis in both U937 and KG1a cells. These findings indicate that the SPM-ceramide pathway is altered in KG1a cells upstream of the ceramide generation. Analysis of the transverse distribution of SPM in the plasma membrane showed that the SPM pool involved in cell signaling (inner leaflet) was markedly reduced in KG1a cells; it is 7-fold lower than that found in the inner leaflet of U937 cells. Therefore, our study strongly suggests that the different responses induced by TNF alpha in myeloid cells are dependent on the SPM plasma membrane transverse asymmetry.

Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates

1991 ◽  
Vol 261 (2) ◽  
pp. R442-R452 ◽  
Author(s):  
E. Fischer ◽  
M. A. Marano ◽  
A. E. Barber ◽  
A. Hudson ◽  
K. Lee ◽  
...  
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Phase Reaction ◽  
Necrosis Factor Alpha ◽  
Hormonal Responses ◽  
Alpha Response ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

Interleukin (IL)-1 is an early mediator of host response to inflammation, although its contribution to individual components of the acute phase reaction is still unclear. To evaluate how the hemodynamic, metabolic, and hormonal responses to sublethal endotoxemia compare with IL-1 administration, baboons received intravenously either lipopolysaccharide (LPS) or 0.1, 10, or 100 micrograms/kg IL-1 alpha. LPS induced an early tachycardia and a fall in mean arterial pressure, as well as lacticacidemia and hypoaminoacidemia. Similar hemodynamic and metabolic changes were seen with 10 or 100 micrograms/kg of IL-1 alpha. An increase in adrenocorticotropic hormone and fall in serum iron were induced by IL-1 alpha but not by LPS. Plasma tumor necrosis factor-alpha (TNF-alpha) was not measurable after IL-1 alpha administration, whereas LPS induced a monophasic TNF-alpha response. IL-6 levels were significantly greater after LPS than IL-1 alpha administration. Histopathological lesions, similar in LPS- and 100 micrograms/kg IL-1 alpha-treated groups, were present only in the adrenal cortex. We conclude that many, but not all, of the effects of sublethal endotoxemia can be replicated by IL-1 alpha administration, and these responses are dose dependent.

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