Cytokine activities in brain have a profound impact on neuroregulation, neurochemistry, behavioural manifestations, modulation of the neuroendocrine and autonomic systems, and neu-rophysiological responses . Cytokines also modulate peripheral gastrointestinal, metabolic (catabolic) and endocrine systems that can impact CNS responses. In diseases associated with wasting and cachexia such as cancer, cytokine deregulation has been extensively studied.
Endogenous cytokines are aberrantly produced in many cancers and by endogenous organs/tissues. In cancer, cytokines can serve as paracrine/autocrine factors (within the neoplastic process and within organs including the brain) or as endocrine signals (from the periphery to brain).
Data suggest that peripherally and centrally (brain) derived cytokines (e.g. IL-1) play a key role in the induction of behavioural and neurological manifestations. Brain cytokine action on neural networks processing can be direct, via modulation of neurons (through glial-neuronal interactions or via modulation of neuronal ion channels, e.g. calcium, sodium, potassium), or indirect, via neurochemical modifications [11,27].
Multiple classes of cytokines have been proposed to participate in the induction and development of wasting and cachexia including via brain mechanisms. These comprise: IL-1, IL-6 subfamily members including CNTF and leukaemia inhibitory factor, IFN-y, TNF-a and BDNF, which in many cases also induce anorexia [9,11,14, 28]. Studies have shown that intratumoral administration of IL-1 receptor antagonist significantly reduces the cachexia associated with a colon tumour , and that treatment of rodents bearing methylcholanthrene-induced sarcoma with monoclonal antibodies against the IL-1 receptor inhibits tumour growth and improves their food intake . In addition to these examples of inoculation with cytokine-producing tumour cells and passive immunisation against cytokines, other relevant data are available from transgenic animals overexpressing cytokines and from transplants of malignant tumours.
Cytokine production triggered within brain -including that activated in brain in response to a peripheral insult - can result in a multi-cytokine interaction network. This brain network can be sustained through positive feedback systems and paracrine/autocrine interactions among brain cells [21,31].
Proinflammatory cytokines modulate gastrointestinal activities (e.g. gastric motility and emptying) including via brain mechanisms by signalling through autonomic nervous system outflow. Cytokines also induce the release of other mediators such as hormones including corti-cotropin-releasing factor, cholecystokinin, glucagon and insulin. As mentioned, cytokines also induce metabolic changes and alterations in lipid, carbohydrate and amino acid metabolism. These cytokine-mediated endocrine and metabolic alterations could be involved in modulating brain responses during wasting and cachexia. Since increased resting energy expenditure can occur during wasting and cachexia, even with a reduced dietary intake, a systemic dysregulation of host metabolism could certainly be influenced by autonomic nervous system outflows.
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