Role of tumor necrosis factor in macrophage leishmanicidal activity in vitro and resistance to cutaneous leishmaniasis in vivo.

This paper will deal with the role of tumor necrosis factor (TNF) in the pathogenesis of various diseases. However, it will be important to remember that originally TNF was characterized as an antitumor factor. In fact, it was known that endotoxin was able to induce hemorrhagic necrosis of some tumors in mice. In 1975 Carswell et al. demonstrated the presence of a tumor necrotizing activity (termed “tumor necrosis serum”) in the sera of mice primed with C. parvum or BCG, and subsequently injected with endotoxin (1). Later it was found that this factor was a macrophage product and was termed TNF. In vivo TNF induced hemorrhagic necrosis of Meth A sarcoma and in vitro demonstrated cytotoxic activity against various tumor cell lines (2). In 1984, TNF was purified and its cDNA was cloned, and the production of substantial amounts of recombinant TNF allowed the characterization of its various biological activities (3). In parallel to these studies on tumor necrosis, the group of Cerami, at the Rockefeller University in New York was studying the mechanisms of cachexia and wasting associated with infection. They found that infection or injection of endotoxin in laboratory animals resulted in a marked hypertrygliceridemia, which was associated with an inhibition of lipoprotein lipase. They hypothesized that a host-derived mediator was responsible for this and other metabolic derangements observed in infection. This factor, which was termed “cachectin”, was later found to be produced by macrophages, and once it was purified and sequenced it became clear that TNF and cachectin were identical (4).

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.354 ◽

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.

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Effect of Tumor Necrosis Factor on Growth of Trypanosoma Musculi in Vivo and in Vitro

Host Defenses and Immunomodulation to Intracellular Pathogens - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4757-5421-6_26 ◽

1988 ◽

pp. 257-262 ◽

Cited By ~ 2

Author(s):

Patricia A. L. Kongshavn ◽

Esfandiar Ghadirian

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Necrosis Factor

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

Endocrinology ◽

10.1210/endo.139.5.6012 ◽

1998 ◽

Vol 139 (5) ◽

pp. 2278-2283 ◽

Cited By ~ 66

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

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.6.h2535 ◽

1994 ◽

Vol 266 (6) ◽

pp. H2535-H2541 ◽

Cited By ~ 16

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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Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus

Blood ◽

10.1182/blood.v76.5.1046.1046 ◽

1990 ◽

Vol 76 (5) ◽

pp. 1046-1053 ◽

Cited By ~ 10

Author(s):

AS Duncombe ◽

A Meager ◽

HG Prentice ◽

JE Grundy ◽

HE Heslop ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Tumor Necrosis Factor ◽

Marrow Transplantation ◽

Tumor Necrosis ◽

Gamma Interferon ◽

Cmv Infection ◽

Necrosis Factor

Abstract After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

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Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.255.2.e206 ◽

1988 ◽

Vol 255 (2) ◽

pp. E206-E212

Author(s):

R. S. Warren ◽

H. F. Starnes ◽

N. Alcock ◽

S. Calvano ◽

M. F. Brennan

Keyword(s):

Tumor Necrosis Factor ◽

Trace Metal ◽

Acute Phase ◽

Acute Phase Response ◽

Tumor Necrosis ◽

Metabolic Response ◽

Zinc Transport ◽

Necrosis Factor

Tumor necrosis factor (TNF; cachectin) has been implicated as a mediator of the toxic manifestations of overwhelming bacterial infection as well as the chronic catabolic state of cancer cachexia. We have examined the acute metabolic and hormonal response after administration of recombinant human TNF in the rat. TNF given by intraperitoneal injection produced dose- and time-related increases in hepatic amino acid uptake, decreases in serum trace metal concentrations, and a pattern of endocrine hormone alterations characteristic of the acute phase response to tissue injury. In vitro zinc transport studies by rat hepatocytes cultured in the presence of TNF alone, or in combination with recombinant human interleukin 1, another mediator of the acute phase response, demonstrated that neither monokine was capable of directly stimulating zinc transport into cells. These findings suggest that TNF may function as an endogenous mediator of the early metabolic response to sepsis and that the trace metal changes induced by TNF in vivo may occur through a secondary mechanism.

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Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice

Blood ◽

10.1182/blood.v74.1.130.130 ◽

1989 ◽

Vol 74 (1) ◽

pp. 130-138 ◽

Cited By ~ 113

Author(s):

RA Johnson ◽

TA Waddelow ◽

J Caro ◽

A Oliff ◽

GD Roodman

Keyword(s):

Tumor Necrosis Factor ◽

Nude Mice ◽

Tumor Necrosis ◽

Chinese Hamster ◽

Anemia Of Chronic Disease ◽

Produce Tumor Necrosis Factor ◽

Tnf Gene ◽

Necrosis Factor

Abstract The anemia of chronic disease (ACD) is associated with conditions in which macrophage activation occurs. Activated marrow macrophages suppress erythropoiesis in vitro and produce tumor necrosis factor (TNF). Therefore, we tested the effects of chronic in vivo exposure to TNF to determine if it was a candidate for a mediator of ACD. Nude mice were inoculated with Chinese hamster ovary (CHO) cells expressing the human TNF gene or with control cells containing the transfection vector alone. The TNF mice promptly became reticulocytopenic, and after 3 weeks their corrected reticulocytes were 2.6% +/- 0.7% as compared with 7.3% +/- 4% in control mice. The hematocrit at 3 weeks was 28.4% +/- 1.7% in TNF mice as compared with 46% +/- 0.8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin (Epo) levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice and had M-colony-stimulating factor (CSF) activity in their serum. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2 +/- 0.2 x 10(3) v 8.6 +/- 0.2 x 10(4) CFU-E per femur, and 6.5 +/- 1 x 10(2) v 8.5 +/- 0.2 x 10(4) BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. The residual BFU-E in TNF mice were relatively resistant to TNF as compared with control mice. These data demonstrate that TNF preferentially inhibits erythropoiesis in vivo and may be important in the pathogenesis of ACD.

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