Cytokines play a key role in the activation of the immune system and the inflammatory response typical of the catabolic state [39-41]. Different experimental approaches have demonstrated that cytokines are able to induce weight loss. They initiate a cascade of events that ultimately leads to a state of wasting, malnourishment, and eventually death. A number of pro-inflammatory cytokines, including IL-1, TNF-a, and interferon (IFN)-y, have been isolated in tumours, as shown in Fig. 4 . These cytokines together with IL-6, leukaemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) are also implicated in the aetiology of cancer anorexia-cachexia syndrome [6,7].
A variety of tumours and peri-tumour cells release these cytokines into the circulation . Elevated serum concentrations of IL-1, IL-6, and TNF- a occur in cancer patients and the concentrations of these cytokines correlate with tumour progression [4, 42, 43]. Furthermore, peripherally circulating cytokines stimulate receptors in the liver, and cytokine induction in this organ provides a reliable indication of peripheral immune activation . At the same time, cytokines cross the blood-brain barrier to activate CNS cytokine systems via specific receptors in the brain (Fig. 5). Cytokines acts directly on the hypothalamus  and indirectly on hypothalamic monoaminergic  neurotransmitters to induce a variety of behavioural manifestations, including anorexia,
CLL HIP HYP
AcP U -IL-IRa hActin
Fig. 5. a Interleukin-1ß (IL-1 ß), IL-1 receptor type I (IL-1RI), IL-1 receptor accessory protein type I (AcP I), IL-1 receptor accessory protein type II (AcP II), transforming growth factor-ß1 (TGF-ß1), and cyclophilin mRNA levels in the cerebellum (CLL), hippocampus (HIP), and hypothalamus (HYP). Male Fischer MCA sarcoma rats (+) or controls (-). b AcP II, IL-1Ra, and actin mRNA levels in the liver of MCA sarcoma rats (lanes 1-3) or controls (lanes 4-6). Brain and liver tissue samples were collected 11 days after tumour-cell inoculation or in controls. Levels of AcP I (membrane-bound), and AcP II (soluble form) and IL-1Ra were not significantly changed in the hypothalamus, hippocampus, and cerebellum. In contrast, levels of AcP II and IL-1Ra mRNAs were significantly up-regulated in the liver of TB rats compared to control. (From )
cognitive and motor deficits, decreased performance in verbal and visual-spatial memory tasks, and poor motor coordination. These behavioural manifestations are due to the effects of cytokines on the hypothalamus, hippocampus, and cerebellum (Fig. 6a, b) and are accompanied by whole-brain and hypothalamic immunohistochemically identifiable changes in monoaminergic and pep-tidergic systems [7,36,48,49].
12 CU Control
12 CU Control
Fig.6. a IL-1| mRNA levels in controls (open bars) or MCA tumour-bearing rats (closed bars). Values (means ± SE; n = 8 for each group) were standardised to arbitrary units. CLL, cerebellum, HIP hippocampus, HYP hypothalamus. * p < 0.05 from pair-fed controls. b Liver mRNA levels of IL-1RI, IL-1R AcP II, and IL-1 Ra in controls (open bars) or MCA tumour-bearing rats (closed bars).Values (means ± SE; n = 8 for each group) were standardised to arbitrary units. * p < 0.05 from pair-fed controls. (From )
Several hypothalamic nuclei working in an integrated function are involved in the control of food intake. Among the different brain nuclei and areas, the VMH appears to play a major role in both cancer and IL-1-induced anorexia. Evidence from our laboratory showed that the functional ablation of VMH, where mRNAs for both IL-1 and IL-1 receptors are detected, reverses established cancer anorexia . More recent data indicated that the intra-VMH injection of IL-1-receptor antagonist (IL-Ra) significantly improves food intake in anorectic tumour-bearing rats . These data strongly support the concept that cancer anorexia is primarily mediated by the direct action of IL-1 on the VMH.
Most cytokines act predominantly through paracrine mechanisms, which suggests that their involvement in cancer-related clinical manifestations is mostly due to their local synthesis within the organs, such as in the brain. In a rat methyl-cholanthrene (MCA)-induced tumour-bearing model, we demonstrated that the IL-1 concentration in the CSF inversely correlates with food intake , while administration of an IL-1| antagonist alleviates anorexia . We also measured specific components of the cytokine-induced anorectic reaction and found: (1) production of detectable levels of mRNA for the proinflammatory cytokines IL-1|, TNF-a, and IFN)-y by the tumour tissue at the onset of anorexia; (2) significantly increased levels of IL-1| and IL-1-receptor type 1 (IL-1RI) mRNA in the hypothalamus, cerebellum, and hippocampus; (3) non-detectable changes in anti-inflammatory IL-1Ra and TGF-|1 mRNA in the regions of the brain studied; and (4) increased levels of IL-1Ra and IL-1-receptor accessory protein type II (IL-1RI AcP II) in the liver of TB rats (Fig. 5) . These data are consistent with the suggestion that cytokines, particularly IL-1|, play a pivotal role in the inhibition of feeding by providing negative feedback on the hypothalamus [4, 7, 51]. It has been proposed that cytokines inhibit feeding by mimicking the hypothalamic effect of excessive negative feedback signalling via inhibition of the NPY/AgRP orexigenic network, as well as by persistent stimulation of the pro-
opiomelanocortin (POMC) anorexigenic pathway . Serotonin (5-HT) has also been demonstrated to inhibit food intake, since in normal rats peripherally infused IL-1 increases brain tryptophan concentrations, probably facilitating competitive crossing of the latter through the blood-brain barrier, consequently increasing 5-HT synthesis [42, 53]. But, more importantly, IL-1 increases 5-HT release by a physiological cascade, whereby the sum of its cytokine and tryptophan determinants amplifies 5-HT release . Experimental data indicate 5-HT's influence via 5-HT1B receptors on magnocellular hypothalamic nuclei during cancer anorexia development, which may contribute to the decrease in food intake in cancer patients [55-57].
Recent data suggest that hypothalamic seroton-ergic neurotransmission is critical in linking cytokines and the melanocortin system. Fenfluramine is a 5-HT agonist that was once widely prescribed in the treatment of obesity to suppress appetite. Fenfluramine increases hypo-thalamic 5-HT concentrations, which in turn activate POMC neurons in the arcuate nucleus, thereby inducing anorexia and reducing food intake [55, 57]. In contrast, cytokines, particularly IL-1, stimulate the release of hypothalamic 5-HT . Thus, it could be speculated that, during tumour growth, cytokines increase serotonergic activity, which, in turn, persistently activates POMC neurons, leading to the onset of anorexia and reduced food intake. Our studies in anorectic rats show that after the tumour is resected, food intake normalises (Fig. 7). When this occurred, normalisation of the 5-HTib receptor and NPY expression in the hypothalamus after tumour resection in tumour-bearing rats was documented using immunocytochemical visualisation of antigens and semi-quantitative image analysis  (Fig. 8).
Since each anorexigenic cytokine family uses a different transducing system, cytokine-induced anorexia is a complex phenomenon that involves many signalling pathways . It is unlikely that they represent separate and distinct pathogenic mechanisms; rather, it appears that close interrelationships exist among them.
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