Interleukin-1-induced anorexia in the rat. Influence of prostaglandins.

Hellerstein, M. K.; Meydani, S N; Meydani, Mohsen; Wu, Ken; Dinarello, C A

doi:10.1172/jci114145

Cited by 306 publications

(123 citation statements)

References 51 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…Similar material has also been detected in the plasma of cancer patients with weight loss greater than 10% (Belizario et al, 1991). The nature of this material is not known, although some studies have suggested that the cytokines tumour necrosis factor alpha (TNF-a) (Flores et al, 1989), alone or in combination with interleukin-1 (Hellerstein et al, 1989) Muscle from non tumour-bearing animal potential candidate for this role is the polyunsaturated fatty acid arachidonic acid. Arachidonate has been shown to both inhibit protein synthesis (Rotman et al, 1992) and increase protein degradation in skeletal muscle (Rodeman & Goldberg, 1982), the latter by the mediation of a prostaglandin E2 (PGE2) intermediate.…”

Section: Discussionmentioning

confidence: 86%

Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia

Smith

Tisdale²

1993

Br J Cancer

116

View full text Add to dashboard Cite

Summary The effects of progressive cachexia on protein metabolism in skeletal muscle has been investigated in mice bearing the MAC 16 adenocarcinoma which produces cachexia with tumour burdens of <1 % of the host weight. Weight loss was accompanied by loss of whole body nitrogen in proportion to the overall loss of body mass. phenylalanine to label proteins in gastrocnemious muscle, a significant depression (60%) in protein synthesis occurred in animals with a weight loss between 15 and 30% accompanied by an increase in protein degradation, which increased with increasing weight loss between 15 and 30%. Muscle degradation in vitro could be achieved by serum from cachectic animals, which appeared to contain a proteolysis-inducing factor. These results suggest that the increased degradation of skeletal muscle seen in this model of cachexia may be due to a circulating proteolysis-inducing factor.Cancer cachexia is a syndrome of progressive of weight loss, with erosion of host body tissues, in particular adipose tissue and muscle in response to tumour growth. Depletion of visceral protein and lean body mass (as assessed by serum albumin and creatinine:height index) have a worse prognostic impact than depletion of adipose tissue, and the greater the weight loss the poorer the prognosis and the lower the response rate to chemotherapy (De Wys, 1986).Skeletal muscle mass declines during the progression of cachexia and white or phasic muscle tends to atrophy more rapidly than red or tonic muscle (Clark & Goodlad, 1971 containing 50 p Ci of L-[4-3H] phenylalanine (specific activity, 46.3 mCi mmol-') (Amersham International, Amersham, UK) was added and the muscles were incubated for a further 2 h with continuous gassing. At the end of the final incubation period the muscles were rinsed in nonradioactive medium, blotted, and homogenised in 3 ml 2% HC104. The homogenate was centrifuged at 2,800 g for 15 min and the supernatant was added to saturated tripotassium citrate (1.5 ml) to give a pH close to 6.0. The insoluble potassium perchlorate was removed by centrifugation and the radioactivity in the supernatant was determined after dilution (1:1) to given the intracellular free pool of L-[4-3H]]phenylalanine.The precipitate from the original centrifugation was washed three times with 5 ml 2% HC104 and hydrolysed in 5 ml 6 N HCl at 10°C in sealed glass tubes for 24 h. The hydrolysates were evaporated to dryness and the residue was dissolved in 10 ml distilled water. A 1 ml sample of the solution was added to 10 ml Optiphase Hi-safe 3 scintillation fluid (FSA Laboratory Supplies, Loughborough, UK) for determination of the protein bound radioactivity. The rate of protein synthesis was calculated by dividing the amount of protein bound radioactivity by the amount of acid soluble radioactivity.Measurement ofprotein degradation Female NMRI mice from the same group used to measure protein synthesis were injected i.p. with 0.25 ml of isotonic saline containing 150 g Ci of L-[4-3H]phenylalanine (sp. act. 1.5 Ci mmol-'). At 24 h after ...

show abstract

Section: Discussionmentioning

confidence: 86%

Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia

Smith

Tisdale²

1993

Br J Cancer

116

View full text Add to dashboard Cite

show abstract

“…Some studies suggest that the cytokine tumour necrosis factor alpha (TNF-a) (Flores et al, 1989) alone, or in combination with interleukin-I (IL-l) (Hellerstein et al, 1989) increase muscle proteolysis through a prostaglandin intermediate. A proteolysis-inducing factor has been shown to be present in the plasma proteins of 25 out of 50 cancer patients with weight loss and in five of these samples the bioactivity was partially abrogated with antibodies to recombinant IL-1 (Belizario et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of muscle protein degradation in cancer cachexia

Smith

Tisdale²

1993

Br J Cancer

View full text Add to dashboard Cite

Summary Depletion of skeletal muscle mass in animals bearing an experimental model of cachexia, the MAC16 adenocarcinoma, occurs by a reduction in protein synthesis accompanied by a large increase in protein degradation. Serum from mice bearing the MAC16 tumour produced an increased protein degradation in isolated gastrocnemius muscle, as measured by tyrosine release, with a maximal effect occurring with serum from animals with a weight loss of between and 20%. The response was specific to the cachectic state, since serum from mice bearing the MAC13 adenocarcinoma, which does not produce weight loss, did not increase tyrosine release from gastrocnemius muscle above that observed with serum from non tumour-bearing animals. The circulatory proteolysis-inducing factor was stable to heating at 60°C for 5 min and was not inhibited by phenylmethylsulfonyl fluoride, suggesting that it was not a serine protease. Female NMRI mice were killed by cervical dislocation and their gastrocnemius muscles were quickly ligated, dissected out and placed in ice-cold isotonic saline. For the experiment presented in Figure 6 animals were administered pure EPA (2 g per kg per day) orally for 5 days prior to the isolation of the gastrocnemius muscle. All animals were sacrificed between 9-10a.m. to minimise diurnal variation and were assured to be in the fed state. The muscles were then blotted, weighed and carefully tied via tendon ligatures (Wu & Thompson, 1988) to stainless steel incubation supports to prevent contraction, thus improving protein balance and Correspondence: M.J. Tisdale.

show abstract

“…However, eicosanoids appear to be involved in these responses, because the reductions in ingestive behavior induced by IL-1 are largely prevented by COX inhibitors, such as indomethacin [183,186]. However, such inhibitors are less effective against the LPS-induced behavioral changes [183,187], and have only small effects on the behavioral changes associated with influenza virus infection [183].…”

Section: The Neurochemical Involvement In Behavioral Responses To Cytmentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

285

169

View full text Add to dashboard Cite

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

show abstract

Interleukin-1-induced anorexia in the rat. Influence of prostaglandins.

Cited by 306 publications

References 51 publications

Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia

Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia

Mechanism of muscle protein degradation in cancer cachexia

Effects of cytokines and infections on brain neurochemistry

Contact Info

Product

Resources

About