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Cytokines play a key role in the activation of the immune system and inflammatory response seen in anorexia [39, 40]. 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. As shown in Fig. 1, cytokines modulate gastric motility and GE, inhibiting food intake. Their effect on the GI system is mediated directly or indirectly via the brain through efferent signals from the autonomic nervous system [41]. Cytokines also induce the release of hormones that act as physiological satiety signals, such as CCK, glucagon, insulin, and leptin. In addition, cytokines activate cascades that induce the production and release of other cytokines, and their interaction with other peptides is also pivotal [42,43], e.g. NPY blocks cytokine-induced anorexia, while cytokines block NPY-induced feeding [44]. There are also reciprocal interactions among cytokines, leptin, NPY, corticotropin-releasing factor (CRH), and glucocorticoids. Pro-inflammatory cytokines, including IL-1, IL-6, and TNF-a, play an important role in the aetiology of CACS [45-48]. These cytokines act directly on the hypothalamus [49] and indirectly on hypothalamic monoaminer-gic neurotransmitters [50] to reduce food intake [47, 51]. There are specific receptors for cytokines in the CNS and peripheral cytokines actively cross the blood brain-barrier to activate the central cytokine system [49]. Cytokines also act on several GI hormones, neuropeptides, and monoamines to delay gastrointestinal motility, and affect gastric motility and intestinal function to induce malabsorption. Cytokines can induce anorexia by producing early satiety, a phenomenon frequently observed during CACS. This has been extensively studied in our laboratory and, as shown in Fig. 7, early satiety initially involves a greater reduction in meal number than in meal size [52,53].

Using our tumour-bearing-rat anorexia model, we demonstrated that increased IL-1 in the CSF inversely correlates with food intake [45] (Fig. 4), while administration of an IL-1p receptor antago

Fig.4. Significant negative correlation between food intake and cerebrospinal fluid (CSF) interleukin (IL)-1a concentrations in anorectic tumour-bearing rats, suggesting a causal relationship between CSF IL-1a and anorexia during cancer. As the concentration of IL-1a in CSF increased, food intake significantly decreased. (From [ 45])

Fig.4. Significant negative correlation between food intake and cerebrospinal fluid (CSF) interleukin (IL)-1a concentrations in anorectic tumour-bearing rats, suggesting a causal relationship between CSF IL-1a and anorexia during cancer. As the concentration of IL-1a in CSF increased, food intake significantly decreased. (From [ 45])

nist (IL-1ra) ameliorates anorexia [54] (Fig. 5). Furthermore, we showed that administration of recombinant human soluble TNF receptor in anorectic tumour-bearing rats led to improvement of food intake with amelioration of anorexia [46] (Fig. 6). It has also been shown that the administration of cytokines to rodents mimics the neurological manifestations observed in cancer patients [49,55,56].

Elevated serum levels of IL-1 have been reported in cancer patients [8]. IL-1 is one of the cytokines produced by macrophages and lymphocytes during acute and chronic pathological processes [43, 49]. In an anorectic rat MCA sarcoma model, we demonstrated that IL-1 concentration in the CSF inversely correlates with food intake [45], and the injection of recombinant human interleukin-1a directly into the ventromedial nucleus (VMN), a food intake regulatory area, decreased food intake [47], while administration of an IL-1ra increased food intake [54] (Fig. 5). Furthermore, the administration of cytokines into rodents mimicked the neurological manifestations observed in cancer patients [45, ,49, 55, 56]. We previously demonstrated that hepatic metabolism of cytokines contributes significantly to food inhibitory signals to the brain [49,57] (Fig. 8).

Peripheral administration of IL-1p inhibits GE of a solid nutrient meal or a non-nutrient solution [58-60]. IL-1ra injected intravenously completely abolishes the delay in GE induced by intravenous IL-1p [15,61]. Suto et al. [60,61] also reported that IL-1p-induced inhibition of GE mediated by brain CRF pathways requires the prostaglandin pathways. Peripheral IL-1p induces PGE2 release in the brain and activates the hypothalamic CRF pathways. CRF released endogenously by various stressors or central injection of CRF acts in the par-aventricular nucleus (PVN) and the dorsal motor nucleus (DMN) of the vagus to inhibit gastric motor function through autonomic pathways [62]. The delay of GE induced by intravenous IL-1p was prevented by injection of ibuprofen, an inhibitor of prostaglandin synthesis [59], and by intracisternal injection of CRF antagonist, as shown in Fig. 9. IL-1a also slows down GE and decreases food intake [63] via significantly increased plasma CCK. Pretreatment with CCK-A (peripheral type) recep-

Fig. 5. Mean ± SE of food intake (g per 24 h) for each study group before and after IL-1 receptor antagonist (IL-1ra) injection. Data are presented as a function of ventromedial nucleus (VMN) microinjection day (day 0). Vertical line Approximate time of VMN microinjection during day 0. Following injection of IL-1ra into the VMN of anorectic tumour-bearing rats (TB-IL-lra), food intake increased. Asterisk indicates significant differences between tumour-bearing rats injected with bovine serum albumin (TB-BSA) and TB-IL-1ra groups. (From [54])

Fig. 5. Mean ± SE of food intake (g per 24 h) for each study group before and after IL-1 receptor antagonist (IL-1ra) injection. Data are presented as a function of ventromedial nucleus (VMN) microinjection day (day 0). Vertical line Approximate time of VMN microinjection during day 0. Following injection of IL-1ra into the VMN of anorectic tumour-bearing rats (TB-IL-lra), food intake increased. Asterisk indicates significant differences between tumour-bearing rats injected with bovine serum albumin (TB-BSA) and TB-IL-1ra groups. (From [54])

Fig. 6. Food intake in a tumour-bearing rat vs control. On infusing tumour necrosis-a (TNF) inhibitor, food intake improved by a significant increase with respect to meal number and size. Plot symbols show means ± SE of A food intake, B meal number, C meal size for the TNF inhibitor and control (vehicle) groups. Asterisk indicates significant differences (p < 0.01) between the two groups for the entire study period. (From [49])

Fig. 6. Food intake in a tumour-bearing rat vs control. On infusing tumour necrosis-a (TNF) inhibitor, food intake improved by a significant increase with respect to meal number and size. Plot symbols show means ± SE of A food intake, B meal number, C meal size for the TNF inhibitor and control (vehicle) groups. Asterisk indicates significant differences (p < 0.01) between the two groups for the entire study period. (From [49])

tor antagonist partially blocked the decrease in food intake and slowed the GE rate by IL-1a [63]. However, there is a report that IL-1 p directly blocks the absorption ability of the small intestine. Kreydiyyeh et al. [64] showed that IL-1p inhibited the mucosal uptake of [14C] 3-O-methylglucose and the intestinal Na+-K+ ATPase. They concluded that the effect of IL-1p on hexose transport across the brush-border membrane could be attributed to its inhibitory effect on the Na+-K+ ATPase.

TNF-a is one of the representative cytokines that induce CACS, and is also the original 'cachectin' [17, 65]. TNF-a is produced by blood monocytes and tissue macrophages in response to the tumour as well as by the tumour itself [66] (see Fig. 4 in the chapter by Ramos et al.). TNF-a acts directly on the CNS to produce its anorectic effect by crossing the blood-brain barrier [67] and suppresses food intake in a dose-dependent manner [68]. By contrast, injection of the soluble pegylated analogue of TNF receptor increases food intake in cancer anorexic rats [47]. Intravenous administration of recombinant TNF-a to rats decreases the rate of intestinal glucose absorption [69], and delays the rate of GE [18, 69, 70]. The nucleus of the solitary tract (NST) in the medulla oblongata is possibly one locus for TNF-a action to control gastrointestinal function [70]. NST receives GI afferents via the vagus and these inhibit DMN stimulation of vagal input to the stomach. TNF-a induces persistent gastric stasis by functioning as a hormone that modulates intrinsic vago-vagal reflex, as shown in Fig. 9 [18].

As shown schematically in Fig. 1, CCK is involved in the functioning of the endocrine cells in the upper small intestine, principally acting to stimulate gallbladder contraction [71] and pancreatic secretion [72], and to delay GE after meals [73, 74]. CCK-induced anorexia is mediated via activation of afferent vagus nerve activity [75-77]. It has been shown that subdiaphragmatic vagotomy blocks the inhibitory effect of intraperitoneal injection of CCK on food intake [78]. Intraduodenal nutrients stimulate the release of CCK from the epithelial endocrine cells. CCK acts on the vagal afferent neurons through CCK-A

Fig. 7. With the onset of anorexia, total and day/night food intake decrease, primarily via a decrease in meal number. While there is an initial compensatory increase in meal size, this too eventually decreases, resulting in profound anorexia. These and similar data suggest that meal number and meal size are regulated independently and are influenced independently via cytokines. a Mean food intake, b meal number, c meal size on the last day of normal food intake (-3) and for the first 3 days (-2,-1,0) of anorexia during the day and night. Data for days +1 and +2 are also shown. (From [53])

Fig. 7. With the onset of anorexia, total and day/night food intake decrease, primarily via a decrease in meal number. While there is an initial compensatory increase in meal size, this too eventually decreases, resulting in profound anorexia. These and similar data suggest that meal number and meal size are regulated independently and are influenced independently via cytokines. a Mean food intake, b meal number, c meal size on the last day of normal food intake (-3) and for the first 3 days (-2,-1,0) of anorexia during the day and night. Data for days +1 and +2 are also shown. (From [53])

Fig. 8. Liver cytokine induction provides a reliable indication of peripheral immune activation. Analysis of both of these components and their comparison with changes in the hypothalamus shed light on cancer anorexia. 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 (closed bars) rats. Values (means ± SE; n = 8 for each group) were standardised to arbitrary units. * p < 0.05 from pair-fed controls. (From [49])

Fig. 8. Liver cytokine induction provides a reliable indication of peripheral immune activation. Analysis of both of these components and their comparison with changes in the hypothalamus shed light on cancer anorexia. 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 (closed bars) rats. Values (means ± SE; n = 8 for each group) were standardised to arbitrary units. * p < 0.05 from pair-fed controls. (From [49])

Fig. 9. Regulation of gastric emptying and small-intestinal absorption in cancer patients. Solid line Stimulation, broken line means inhibition. PVN, paraventricular nucleus; NST, nucleus of the solitary tract; DMN, dorsal motor nucleus

Vagal Afferent

TNFa

CCK IL^Ia

Vagal Efferent

Gastric Emptying

Small Bowel Absorption

receptors and signals are transported to the dorsal vagal complex. The information is relayed to vagal efferent neurons to induce gastric relaxation [33]. CCK may act either locally or via the circulation to stimulate vagal afferent fibre discharge to regulate the emptying of gastric content [79]. Injection of IL-1 reduces food intake and GE in healthy animals via an increase in plasma CCK, and pretreat-ment with CCK receptor antagonist partially blocks this gastric stasis, suggesting that CCK mediates IL-1a-induced anorexia (Fig. 9).

Convergent information suggests that CRF is involved in the changes observed in GI motility during stress exposure, which is a likely cause of CRF-induced delayed GE and gastric stasis in cancer patients (Fig. 1).

CRF can induce stress-related responses, including anorexia and anxiety-like behaviours [80]. Hypothalamic CRF levels are higher in tumour-bearing rats than in a pair-fed control group, suggesting that the CRF system is activated in cancer anorexia [81]. CRF injected into the cis-

terna magna or the lateral ventricle inhibits GE of liquid and solid meals in various experimental animals, including rats and mice [62, 82]. The responsive brain sites for CRF to influence gastric motor function are the PVN and the dorsoventral centre (DVC) [62]. CRF antagonists such as a-heli-cal CRF9-41 and astressin, when injected into the CSF, blocked CRF-induced inhibition of GE, indicating specific interactions with CRF receptors in the brain [83].

Thus, IL-1p-induced inhibition of GR is mediated by brain CRF pathways. CRF acts in the PVN and the DMN of the vagus to inhibit gastric motor function through autonomic pathways [60,61].

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