scholarly journals Effect of recombinant human tumour necrosis factor α on protein synthesis in liver, skeletal muscle and skin of rats

1989 ◽  
Vol 258 (2) ◽  
pp. 493-497 ◽  
Author(s):  
Y Charters ◽  
R F Grimble
Keyword(s):  
Protein Synthesis ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Muscle Protein ◽  
Liver Protein ◽  
Post Injection ◽  
Synthetic Rate ◽  
Rna Content ◽  
Tibialis Muscle ◽  
Necrosis Factor

Bacterial endotoxins cause enhanced protein metabolism in liver, and protein catabolism in muscle and skin. These effects may be mediated by cytokines such as interleukin 1 (IL1) and tumour necrosis factor (TNF). The study investigates the timing and magnitude of effects of recombinant human TNF alpha on protein synthesis and protein and RNA content of the liver, tibialis muscle and skin of Wistar rats. Intravenous doses of 30 and 300 micrograms/kg of body weight were used and effects examined 8 h and 24 h after injection. Muscle protein content and synthetic rate were reduced at 8 h post-injection by over 18% and 20% respectively. Protein synthesis returned to normal after the lowest dose but remained depressed 24 h after the highest dose due to the accompanying anorexia. Opposite effects were observed in liver. Protein fractional synthetic rate (FSR) was increased by over 26% at 8 h post-injection and remained elevated 24 h after the higher but not lower dose of TNF. Total protein and RNA contents were significantly higher than controls at this time. Skin protein synthesis was unaffected by TNF; however an increase in protein and RNA content was observed at 8 h post-injection with the lower dose of TNF. Liver and muscle respond in a similar but more rapid way to TNF than to endotoxin. The response of skin is however totally different. While muscle may contribute amino acids for enhanced hepatic protein synthesis following exposure to TNF, skin does not.

scholarly journals Pharmacological interference with tissue hypercatabolism in tumour-bearing rats

1994 ◽  
Vol 299 (1) ◽  
pp. 71-78 ◽  
Author(s):  
L Tessitore ◽  
P Costelli ◽  
F M Baccino
Keyword(s):  
Adipose Tissue ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Muscle Protein ◽  
Plasma Corticosterone ◽  
High Plasma ◽  
Liver Protein ◽  
Tissue Mass ◽  
Anabolic Hormone ◽  
Necrosis Factor

Marked loss of body weight and profound waste of both skeletal muscle and white adipose tissue occur in rats into which the ascites hepatoma Yoshida AH-130 has been transplanted, associated with marked perturbations in the hormonal homoeostasis and the presence of circulating tumour necrosis factor and high plasma levels of prostaglandin E2 [Tessitore, Costelli and Baccino (1993) Br. J. Cancer 67, 15-23]. On the basis of previous findings, the present study examined whether the development of cachexia in this model system could be significantly affected by adrenalectomy or by pharmacological treatments that may interfere with proximal or distal mediators of tissue hypercatabolism. In no instance was tumour growth modified. Medroxyprogesterone acetate, an anabolic-hormone-like drug, was completely ineffective. In adrenalectomized animals, although changes such as the elevation of plasma triacylglycerols and corticosterone were corrected, the general course of cachexia was not modified. A partial prevention of muscle waste was observed with acetylsalicylic acid, a non-steroidal anti-inflammatory drug, or with leupeptin, a proteinase inhibitor. Insulin afforded the most significant preservation of muscle protein and adipose-tissue mass, which were maintained close to control values even 10 days after transplantation. The effects of insulin on gastrocnemius muscle and liver protein content were exerted by slowing down protein turnover, mainly enhancing synthesis. Consistently, the total free amino acid concentration in the gastrocnemius of insulin-treated rats 10 days after tumour transplantation was close to that of controls. Although treatment with insulin decreased plasma corticosterone to normal values, it did not modify the circulating level of tumour necrosis factor. On the whole these data show that it seems possible to prevent, at least in part, the tissue waste that characterizes cancer cachexia by purely pharmacological means.

Influence of butter and of corn, coconut and fish oils on the effects of recombinant human tumour necrosis factor-α in rats

1993 ◽  
Vol 84 (1) ◽  
pp. 105-112 ◽  
Author(s):  
Hilda M. Mulrooney ◽  
Robert F. Grimble
Keyword(s):  
Protein Synthesis ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Coconut Oil ◽  
Complement C3 ◽  
Tumour Necrosis Factor Α ◽  
Zinc Concentrations ◽  
Factor Α ◽  
Lung And Kidney ◽  
Necrosis Factor

1. Tumour necrosis factor-α is produced in response to inflammatory stimuli. Fish oil can suppress the production and actions of cytokines. Little information is available on the effects of other fats on cytokine biology. We compared the effects of fats, with a wide range of fatty acid characteristics, on the effects of tumour necrosis factor-α on protein and zinc metabolism in rats. 2. Weanling rats were fed for 8 weeks on diets containing 10% fat in the form of corn, fish or coconut oils or butter before an intraperitoneal injection of recombinant human tumour necrosis factor-α was given. Measurements were made 24 h after the injection. 3. In rats fed corn oil, food intake was reduced by 62% and rates of protein synthesis were increased by 86, 32 and 39% in the liver, lung and kidney, respectively. Zinc concentrations increased by 23% in the liver but decreased by 10% in the kidney. Plasma caeruloplasmin and complement C3 levels increased by 25% and 28%, respectively, and plasma albumin level decreased by 24%. 4. Fish oil prevented the increase in hepatic protein synthesis and changed the response of protein synthesis in lung and kidney to a decrease. Changes in hepatic and renal zinc concentrations were prevented. The response of the plasma caeruloplasmin level was unaltered but those of the plasma complement C3 and albumin concentrations were prevented. 5. Coconut oil and butter, although similarly low in linoleic acid, differed in their modulatory effects. With the exception of the rise in the plasma complement C3 concentration, all responses were prevented or greatly inhibited in rats fed butter. In rats fed coconut oil the increase in liver protein synthesis was reduced but that in the lung and kidney was unaffected. Changes in hepatic zinc concentration were unaffected but those in renal zinc concentration were prevented. 6. Fish and coconut oils and butter reduced the intensity of anorexia caused by tumour necrosis factor-α. The extent to which fats rich in (n-3) polyunsaturates or poor in linoleic acid modulate the metabolic response to tumour necrosis factor-α depends upon additional fatty acid characteristics.

Cardiac Muscle Protein Gene Expression in the Endotoxin-Treated Rat

1994 ◽  
Vol 87 (5) ◽  
pp. 539-546 ◽  
Author(s):  
D. C. Macallan ◽  
G. E. Griffin
Keyword(s):  
Cardiac Muscle ◽  
Myosin Heavy Chain ◽  
Tumour Necrosis Factor ◽  
Heavy Chain ◽  
Tumour Necrosis ◽  
Muscle Protein ◽  
Mrna Levels ◽  
Tumour Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

1. Sepsis is associated with marked changes in cardiac muscle protein synthesis. Such changes may be the result of altered transcription of specific myofibrillar protein mRNAs. 2. In order to investigate myofibrillar protein gene expression, a rat model of sepsis was used. Adult rats were given a single sub-lethal dose of lipopolysaccharide by the intraperitoneal route. At various times thereafter, rats were killed and ventricular muscle was removed. RNA was extracted and transferred to nylon membranes. Changes in expression of mRNA for α- and β-myosin heavy chain, α-actin, cardiac troponin C and carbonic anhydrase III were detected by Northern hybridization. 3. After treatment with lipopolysaccharide, mRNA for β-myosin heavy chain increased to 260% of control values at 24 h and reached a maximum of 310% at 48 h. α-Myosin heavy chain mRNA levels fell to 72% of control values at 24 h. mRNA levels for α-actin, cardiac troponin C and carbonic anhydrase III remained unchanged. 4. In order to investigate the role of tumour necrosis factor-α in this process, some rats were pretreated with monoclonal antibody against tumour necrosis factor-α before receiving lipopolysaccharide. Such animals showed an absence of tumour necrosis factor-α bioactivity in plasma, but changes in myocardial protein mRNA levels were no different from those seen in animals receiving lipopolysaccharide alone. 5. The reduction in protein synthesis in cardiac muscle in sepsis does not appear to be the result of reduced expression of genes for structural or soluble muscle protein. Rather there is a paradoxical increase in β-myosin heavy chain expression, which may represent a protective mechanism. Tumour necrosis factor-α does not appear to be involved in the mediation of these changes.

scholarly journals Increased intestinal protein synthesis during sepsis and following the administration of tumour necrosis factor α or interleukin-1 α

1992 ◽  
Vol 286 (2) ◽  
pp. 585-589 ◽  
Author(s):  
D von Allmen ◽  
P O Hasselgren ◽  
T Higashiguchi ◽  
J Frederick ◽  
O Zamir ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Interleukin 1 ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Jejunal Mucosa ◽  
Ileal Mucosa ◽  
Intestinal Protein ◽  
Necrosis Factor

The influence of sepsis on intestinal protein synthesis was studied in rats. Sepsis was induced by caecal ligation and puncture (CLP); control rats were sham-operated. Protein synthesis was measured in vivo in the jejunum and ileum following a flooding dose of [14C]leucine. At 8 h after CLP the protein synthesis rate was increased by approx. 15% in jejunal mucosa, and at 16 h after CLP, the protein synthesis rate was increased by 50-60% in the mucosa and seromuscular layer of both jejunum and ileum. In a second series of experiments, rats were treated with recombinant tumour necrosis factor alpha (rTNF alpha) or recombinant interleukin-1 alpha (rIL-1 alpha) administered at a total dose of 300 micrograms/kg body weight over 16 h. Control rats received corresponding volumes of solvent. Treatment with rTNF alpha resulted in an approx. 25% increase in mucosal protein synthesis in jejunum. Following treatment with rIL-1 alpha, protein synthesis increased by 25% in jejunal mucosa and almost doubled in ileal mucosa. The results suggest that sepsis stimulates intestinal protein synthesis and that this response may, at least in part, be mediated by TNF and/or IL-1.

scholarly journals Regulation of lipoprotein lipase synthesis in 3T3-L1 adipocytes by cachectin Further proof for identity with tumour necrosis factor

1986 ◽  
Vol 240 (2) ◽  
pp. 601-604 ◽  
Author(s):  
S R Price ◽  
T Olivecrona ◽  
P H Pekala
Keyword(s):  
Protein Synthesis ◽  
Conditioned Medium ◽  
Tumour Necrosis Factor ◽  
Lipoprotein Lipase ◽  
Tumour Necrosis ◽  
Secretory Protein ◽  
Necrosis Factor ◽  
Precipitable Protein

We investigated the mechanism by which the endotoxin-induced macrophage secretory protein cachectin is able to suppress the activity of lipoprotein lipase in 3T3-L1 adipocytes. The loss in activity results from an effect on the synthesis of the enzyme, as determined by a decreased incorporation of [35S]methionine into immunoprecipitable lipoprotein lipase. The results were nearly identical whether crude conditioned medium or a highly purified preparation was utilized as a source of cachectin. [35S]Methionine incorporation into acid-precipitable protein was minimally affected by purified cachectin, suggesting that the suppression of the lipoprotein lipase was not due to a general suppression of protein synthesis. These results, taken together with our previous work, provide additional evidence that cachectin and tumour necrosis factor are functionally identical.

scholarly journals Dietary fat modifies some metabolic actions of human recombinant tumour necrosis factor α in rats

1990 ◽  
Vol 63 (3) ◽  
pp. 653-668 ◽  
Author(s):  
D. C. Bibby ◽  
R. F. Grimble
Keyword(s):  
Tumour Necrosis Factor ◽  
Rectal Temperature ◽  
Tumour Necrosis ◽  
Coconut Oil ◽  
Liver Protein ◽  
Tumour Necrosis Factor Α ◽  
Zn Content ◽  
Factor Α ◽  
Necrosis Factor ◽  
Maize Oil

To examine how fat might influence the metabolic effects of tumour necrosis factor α (TNFα), human recombinant TNFα was given intravenously to rats that had been fed for 12 weeks on diets containing (g/kg) 200 maize oil or 190 coconut oil+10 maize oil. Rectal temperature and tissue composition measurements were made 8 and 24 h after injection. Ambient temperatures of 20° and 25° were employed to accentuate rectal temperature changes. Doses of 30 and 300 μg TNFα/kg body-weight were given, and brought about depression of serum zinc and albumin and elevation of copper. Muscle protein content was decreased and liver protein and Zn content enhanced by TNFα. Serum Zn and liver Zn content were negatively correlated 8 h after injections. Hypothermia developed within 1 h of injection. All responses except the rise in serum Cu and gain in liver Zn were more intense at the higher than at the lower dose of TNFα. Hypothermia was exacerbated by an environmental temperature of 20°. The coconut-oil diet blunted the hypothermia and likewise the changes in serum albumin and Cu content 8 h after injections and in muscle and liver protein after 24 h. Changes in eicosanoid metabolism may be involved in the modulatory effects of the coconut-oil-enriched diet.

scholarly journals Interferon-α induces sensitization of cells to inhibition of protein synthesis by tumour necrosis factor-related apoptosis-inducing ligand

FEBS Journal ◽  
2006 ◽  
Vol 273 (16) ◽  
pp. 3698-3708 ◽  
Author(s):  
Ian W. Jeffrey ◽  
Androulla Elia ◽  
Stephanie Bornes ◽  
Vivienne J. Tilleray ◽  
Karthiga Gengatharan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Interferon Α ◽  
Inhibition Of Protein Synthesis ◽  
Necrosis Factor

Substrate specificity and inducibility of TACE (tumour necrosis factor α-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity

2003 ◽  
Vol 70 ◽  
pp. 39-52 ◽  
Author(s):  
Roy A. Black ◽  
John R. Doedens ◽  
Rajeev Mahimkar ◽  
Richard Johnson ◽  
Lin Guo ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Recent Work ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Transforming Growth Factor ◽  
Intrinsic Activity ◽  
Converting Enzyme ◽  
Tumour Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

Tumour necrosis factor α (TNFα)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor α, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.

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