Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress.

Table 2 summarizes the reported responses of the HPA axis, as well as catecholamines and indoleamines to the cytokines discussed above. Cytokine administration to animals can elicit a number of effects on the brain, including neuroendocrine and behavioural effects, and also alters the metabolism of neurotransmitters. The most well documented effect is the activation by interleukin-1 (IL-1) of the hypothalamo-pituitary-adrenocortical (HPA) axis, which is accompanied by a stimulation of cerebral noradrenaline (NA) metabolism, probably reflecting increased NA secretion. IL-1 also stimulates indoleamine metabolism, most prominently increasing tryptophan concentrations, and increasing the metabolism of serotonin (5-hydroxytryptamine, 5-HT). IL-6 induces a short-lived activation of the HPA axis, and has effects on tryptophan and 5-HT similar to those of IL-1. Tumour necrosis factor alpha (TNF alpha) has effects on the HPA axis similar to those of IL-6, but affects NA and tryptophan only at high doses. Interferon alpha had no effects on the parameters studied. The effects of IL-1 are remarkably similar to those observed following administration of endotoxin (lipopolysaccharide, LPS), and infections, such as influenza virus. They also resemble quite closely the responses that are observed to stressors commonly studied in laboratory animals, such as electric shock or restraint. The major differences are: that the NA response to shock or restraint is very uniform throughout the brain, whereas that to IL-1, LPS or infection is significantly greater in the hypothalamus; and, responses in dopaminergic (DA) systems are normally observed to shock or restraint, with especially prominent responses in the limbic cortex, whereas DA responses are rarely observed in response to IL-1 and immune stimuli, and when they do occur, the mesocortical system is not selectively affected. The neurochemical responses to cytokines may underlie some of the endocrine and behavioural responses. The NA response to IL-1 is apparently related to the HPA activation, but not the hypophagia. The significance of the indoleaminergic responses is not known.