The Effect of a Metalloproteinase Inhibitor (GI5402) on Tumor Necrosis Factor- (TNF-) and TNF- Receptors During Human Endotoxemia

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Pascale E.P. Dekkers ◽  
Fanny N. Lauw ◽  
Tessa ten Hove ◽  
Anje A. te Velde ◽  
Philip Lumley ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Surface Expression ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Proinflammatory Effect ◽  
Necrosis Factor

Tumor necrosis factor- (TNF-) is released from the cell surface by cleavage of pro–TNF- by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-, but also to enhance the surface expression of TNF- and TNF- receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (−20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF- release (P < .001), but did not influence the increase in monocyte-bound TNF-. In addition, GI5402 attenuated the rise in plasma-soluble TNF- receptors types I and II after LPS injection (both P < .001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF- receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF- is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF- and TNF- receptor number.

scholarly journals Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1607-1613 ◽  
Author(s):  
W Digel ◽  
W Schoniger ◽  
M Stefanic ◽  
H Janssen ◽  
C Buck ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

Abstract Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high- affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.

scholarly journals Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1607-1613
Author(s):  
W Digel ◽  
W Schoniger ◽  
M Stefanic ◽  
H Janssen ◽  
C Buck ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high- affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.

scholarly journals A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon.

1994 ◽  
Vol 179 (4) ◽  
pp. 1185-1191 ◽  
Author(s):  
K J Van Zee ◽  
S A Stackpole ◽  
W J Montegut ◽  
M A Rogy ◽  
S E Calvano ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Lethal Dose ◽  
Human Tumor ◽  
Receptor Activation ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

A number of recent studies have demonstrated that cellular responses to tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF receptors are distinct. To evaluate the relative in vivo toxicities of wild-type TNF alpha (wtTNF alpha) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sp.) were infused with a near-lethal dose of either wtTNF alpha or a TNF alpha double mutant (dmTNF alpha) that binds specifically to the p55, but not to the p75, TNF receptor. Both wtTNF alpha and dmTNF alpha produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wtTNF alpha produced a marked granulocytosis and loss of granulocyte TNF receptors, whereas little if any changes in neutrophil number or cell surface TNF receptor density were seen after dmTNF alpha mutant administration. Infusion of dmTNF alpha resulted in a plasma endogenous TNF alpha response that peaked after 90-120 min. We conclude that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.

Tumor necrosis factor (TNF)–mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1782-1791 ◽  
Author(s):  
Ingunn Dybedal ◽  
David Bryder ◽  
Anna Fossum ◽  
Leiv S. Rusten ◽  
Sten Eirik W. Jacobsen
Keyword(s):  
Bone Marrow ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Scid Mice ◽  
Tnf Receptor ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Necrosis Factor

Abstract Hematopoietic stem cell (HSC) fate decisions between self-renewal and commitment toward differentiation are tightly regulated in vivo. Recent developments in HSC culture and improvements of human HSC assays have facilitated studies of these processes in vitro. Through such studies stimulatory cytokines critically involved in HSC maintenance in vivo have been demonstrated to also promote HSC self-renewing divisions in vitro. Evidence for negative regulators of HSC self-renewal is, however, lacking. Tumor necrosis factor (TNF), if overexpressed, has been implicated to mediate bone marrow suppression. However, whether and how TNF might affect the function of HSC with a combined myeloid and lymphoid reconstitution potential has not been investigated. In the present studies in vitro conditions recently demonstrated to promote HSC self-renewing divisions in vitro were used to study the effect of TNF on human HSCs capable of reconstituting myelopoiesis and lymphopoiesis in nonobese diabetic–severe combined immunodeficient (NOD-SCID) mice. Although all cord blood and adult bone marrow CD34+CD38− cells were capable of undergoing cell divisions in the presence of TNF, cycling HSCs exposed to TNF in vitro and in vivo were severely compromised in their ability to reconstitute NOD-SCID mice and long-term cultures. The negative effect of TNF was not dependent on the Fas pathway, and a similar effect could be observed using a mutant TNF exclusively targeting the p55 TNF receptor. TNF did not appear to enhance apoptosis or affect cell-cycle distribution of cultured progenitors, but rather promoted myeloid differentiation. Thus, TNF might regulate HSC fate by promoting their differentiation rather than self-renewal.

Tumor necrosis factor-α inhibitors alleviation of experimentally induced neuropathic pain is associated with modulation of TNF receptor expression

2014 ◽  
Vol 92 (11) ◽  
pp. 1490-1498 ◽  
Author(s):  
Pablo Andrade ◽  
Govert Hoogland ◽  
John S. Del Rosario ◽  
Harry W. Steinbusch ◽  
Veerle Visser-Vandewalle ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Factor Α ◽  
Necrosis Factor ◽  
Experimentally Induced

Abstract 354: Lower Circulating Levels of Tumor Necrosis Factor Related Apoptosis-inducing Ligand (TRAIL) are Associated with Increased Sub-clinical Coronary Atherosclerosis among Smokers

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aman Gupta ◽  
Divay Chandra ◽  
Yingze Zhang ◽  
Steven Reis ◽  
Frank Sciurba
Keyword(s):  
Tumor Necrosis Factor ◽  
Coronary Atherosclerosis ◽  
Tumor Necrosis ◽  
Smoking Status ◽  
Calcium Score ◽  
Meso Scale Discovery ◽  
The Mean ◽  
Necrosis Factor

Rationale: There is significant in vitro evidence demonstrating anti-atherogenic effect of circulating Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Also, decreased circulating TRAIL levels have been reported in patients with acute myocardial infarction and in those undergoing coronary catheterization due to suspected coronary atherosclerosis. However, it remains unknown if TRAIL levels are associated with sub-clinical coronary atherosclerosis. Methods: The study included 460 current and former smokers enrolled in the Pittsburgh COPD SCCOR study. Serum TRAIL levels were measured by electrochemiluminescence immunoassay, according to the manufacture’s protocol (Meso Scale Discovery, Gaithersburg, Maryland). Coronary atherosclerosis was assessed by a validated visual coronary artery calcium scoring system using non-EKG gated chest CT scans (Weston score). Ordinal logistic regression models were used to identify significant associations between categories of CAC score (0, 1-3, 4-8, and 9-12) and TRAIL level, and to adjust for cardiovascular risk factors. Results: The mean age of the 460 participants was 65.7 ± 6.3 years, 52.2% were male, and the mean pack years of smoking was 55.0 ± 30.8 years. In univariate analyses, each standard deviation decrease in TRAIL levels was associated with 1.42-fold increase in the odds of having calcium scores in one higher category (p<0.001). This association persisted despite adjustment for age, gender, race, body mass index, hypertension, diabetes, hyperlipidemia, pack years of smoking, and current smoking status (adjusted OR for higher category of calcium score per SD decrease in TRAIL level 1.22, p=0.04). Conclusions: Our results expand on the in vitro and in vivo data linking decreased TRAIL levels with increased atherosclerosis by demonstrating a novel association between lower circulating TRAIL and increased subclinical coronary atherosclerosis.

scholarly journals In Vivo and in Vitro Evidence for the Involvement of Tumor Necrosis Factor-α in the Induction of Leptin by Lipopolysaccharide*

Endocrinology ◽  
1998 ◽  
Vol 139 (5) ◽  
pp. 2278-2283 ◽  
Author(s):  
Brian N. Finck ◽  
Keith W. Kelley ◽  
Robert Dantzer ◽  
Rodney W. Johnson
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Retinoids downregulate both p60 and p80 forms of tumor necrosis factor receptors in human histiocytic lymphoma U-937 cells

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3547-3555 ◽  
Author(s):  
K Totpal ◽  
MM Chaturvedi ◽  
R LaPushin ◽  
BB Aggarwal
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukemia Cell Line ◽  
Cell Surface Expression ◽  
Scatchard Analysis ◽  
Dependent Manner ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Histiocytic Lymphoma ◽  
Necrosis Factor

Because retinoids are known to modulate the growth and differentiation effects of tumor necrosis factor (TNF), we investigated the effect of all-trans-retinoic acid (RA) on the cell surface expression of TNF receptors in human histiocytic lymphoma U-937 cells. RA decreased the specific binding of 125I-labeled TNF to these cells in a dose- and time-dependent manner. The maximal decrease occurred when cells were treated with 1 mumol/L RA for 24 hours at 37 degrees C. Scatchard analysis of the binding indicated that the decrease by RA was caused by a decrease in receptor number and not by a decrease in affinity. The downmodulation of TNF receptors was also confirmed by covalent receptor-ligand cross-linking studies. Receptor-mediated internalization of the ligand was also found to be decreased on treatment of cells with RA. Northern blot analysis also indicated a decrease in the transcript of the receptor. By using antibodies specific to either the p60 or p80 form of the TNF receptor, we found that both receptors were downregulated by RA. RA treatment also decreased TNF receptors on acute monocytic leukemia cell line THP-1. Other analogues of RA, specifically 9-cis-RA, (E)-4-[2-(5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoic acid (TTNPB), and 3-methyl-TTNPB, which differ in their specificity towards different RA receptors, were also active in downregulating TNF receptors. 3-Methyl-TTNPB, which is more specific for the RXR form of the RA receptor, was found to be most potent. The downregulation of TNF receptors by RA correlated with the downmodulation of the antiproliferative effects of TNF against U-937 cells. Overall, our results indicate that RA downmodulates both the p60 and p80 form of the TNF receptor on cells of myeloid origin, which correlates with the cellular response.

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation

1994 ◽  
Vol 266 (6) ◽  
pp. H2535-H2541 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Mean Arterial Pressure ◽  
Tumor Necrosis Factor ◽  
Arterial Pressure ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Vascular Relaxation ◽  
Endothelium Dependent Relaxation ◽  
Necrosis Factor

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

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