Proinflammatory Cytokines

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It has been suggested that the chronic action of mediators released by tumour cells and immune cells counteracting tumour is the main cause of the metabolic abnormalities characterising the cachectic neoplastic patient. Indeed, several experimental and clinical researches confirm the central role exerted by proinflammatory cytokines, especially interleukin (IL)-1, IL-6 and TNF-a, in the pathogenesis of CACS. Chronically elevated levels for these factors, either alone or in combination, are capable of reproducing the different features of CACS [10, 11]. More direct evidence of a cytokine involvement in CACS is provided by the observation that cachexia in animal experimental models can be relieved by administration of specific cytokine antagonists [11-13]. These studies revealed that CACS can rarely be attributed to any one cytokine but rather is associated with a set of cytokines that work in concert [3].

The role of IL-1 in the pathogenesis of CACS has been clearly elucidated. IL-1 exerts a specific effect on reducing food intake and influences meal size, meal duration and meal frequency [14, 15]. Hypothalamic IL-1 is increased either through access from the median eminence (a cir-cumventricular nucleus without a blood-brain barrier proximal to the arcuate nucleus) or is generated within the hypothalamus [16]. IL-1 has an anorectic action by directly decreasing neuropep-tide Y (NPY) neurotransmission and secondarily by increasing corticotropin-releasing factor (CRF), which in turn acts on the satiety circuitry inhibiting food intake. In rat models, IL-1 has been demonstrated to inhibit serum levels of growth hormone (GH) by increasing CRF and somatostatin levels [17]. The reduced synthesis of GH leads to reduced synthesis of the insulin-like growth factors (IGFs), which in turn influence the muscle protein turnover and the autocrine and paracrine regulation of muscle mass proliferation [18]. In vitro studies have demonstrated that IGF-1 induces muscle glucose synthesis and amino acid uptake and inhibits protein catabolism [19-21]. Studies on experimental models of rats bearing cachectic tumour showed that the administration of IGF-1 was able to prevent weight loss, muscle wasting and loss of muscle protein. IL-1 also acts peripherally on pancreatic beta cells, which have specific receptors for IL-1 [22]. IL-1 on beta cells first induces the release and synthesis of insulin and, secondarily, inhibits the synthesis and release of insulin [23].

TNF-a has been shown to promote lipolysis and inhibit lipogenesis and plays a key role in the depletion of adipose tissue mass seen in cachexia. It has been proposed that an elevation in plasma levels of TNF-a is responsible for the metabolic alterations in adipose tissue seen in cachexia [24]. Lipid metabolism is a complex sequence of events that determine whether the triglyceride pool within the adipocyte increases, due to the processes of free fatty acid (FFA) uptake and lipo-genesis, or decreases, due to the process of lipoly-sis. Circulating lipoproteins and triglycerides are first converted into FFA by the action of lipopro-tein lipase (LPL), which is secreted by the adipocyte. FFA can then enter the adipocyte via a fatty acid transporter. Once inside the adipocyte, the FFA is converted into the triglyceride by a multi-step-regulated enzymatic reaction, one of the enzymes involved being acyl-CoA synthetase. In addition, triglyceride can be formed from the uptake of glucose, via glucose transporters (GLUT)1 and 4, into the adipocyte. The glucose can then be converted into triglyceride by the actions of a series of enzymes, which include acetyl-CoA carboxylase and fatty acid synthase. A large body of evidence now supports a role for TNF-a in modulating these processes [25]. Studies utilising mammary adipose tissue from human subjects have now shown that TNF-a inhibits LPL activity by down-regulating its protein expression [26]. Indeed, increasing TNF-a mRNA levels are correlated with decreasing LPL activity in human subcutaneous adipose tissue [27]. In addition, TNF-a has been shown to reduce the expression of FFA transporters in adipose tissue of the Syrian hamster [28]. TNF-a could thus hinder the synthesis and entry of FFA into the adipocyte, curtailing an increase in the intracellular triglyceride pool size. Studies have also suggested that TNF-a may decrease the expression of enzymes involved in lipogenesis. Specifically, it has been suggested that acetyl-CoA carboxylase and fatty acid synthase are down-regulated. However, it is unclear if this occurs in mature adipocytes [25]. Acyl-CoA synthase expression and activity have also been suggested to be down-regulated by TNF-a [29]. TNF-a has been found to promote lipolysis. However, the mechanisms by which this is achieved are unclear. TNF-a administration also induces increase of cortisol, glucagon and insulin levels and these effects seem to be mediated by IL-1; the concomitant administration of recombinant IGF-1 reduces the percentage of protein loss by 15% with an associated improvement of glucose metabolism. TNF-a has been implicated as a factor associated with the development of insulin resistance. Studies in women have found a positive association between plasma insulin levels and TNF-a mRNA from subcutaneous adipose tissue [30], which is supported by a study showing increased adipose TNF-a secretion in obese patients with insulin resistance [27]. Extensive research has highlighted several potential mechanisms by which TNF-a induces insulin resistance. These include: accelerated lipolysis and a concomitant increase in circulating FFA concentrations, down-regulation of GLUT4 synthesis, down-regulation of insulin receptor, insulin receptor substrate-1 (IRS-1) synthesis and increased Ser/Thr phosphorylation of IRS-1 [31].

Interleukin-6 is another proinflammatory cytokine with cachectic effects. In an experimental animal model, Strassmann et al. [32] demonstrated that the presence of tumour in mouse models was associated with early CACS and production of IL-6, dosable in the serum. Serum IL-6 levels correlated with the severity of CACS. Moreover, the administration of anti-IL-6 antibody inhibits the appearance of CACS symptoms. In vitro studies have demonstrated that IL-6 induces, similarly to IL-1, the hypothalamic release of CRF. Moreover, IL-6 acts on beta pancreatic cells similarly to IL-1 [33].

Thus, proinflammatory cytokines IL-1, TNF-a and IL-6 play a central role in the pathogenesis of metabolic derangements associated with CACS. It may be hypothesised that, during the initial phases of neoplastic disease, the synthesis of proin-flammatory cytokines leads to an efficient anti-neoplastic effect. However, their chronic activity leads to severe alterations of cell metabolism, with deleterious effects on body composition, nutritional status and immune system efficiency.

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