Effects of cytokines and infections on brain neurochemistry

Abstract

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

“…the selective serotonin reuptake inhibitors (SSRI's) such as fluoxetine, paroxetine and citalopram, SERT represents a potential target for cytokine-induced regulatory mechanisms contributing to the pathophysiological processes underlying depressive illnesses. Indeed, pro-inflammatory cytokines have been implicated in the regulation of serotonergic homeostasis in vivo through the modulation of central serotonin activity and metabolism [20,21]. Studies assessing cytokine-mediated modulation of SERT expression and/or activity have predominately been conducted in SERT expressing cell lines of peripheral origin [4,[22][23][24][25][26].…”

Effects of interleukin-1β and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests

“…Both IL-1 and LPS activate brain norepinephrine and serotonin metabolism (Dunn, 1988;Kabiersch et al, 1988;Dunn, 2006), and activate the hypothalamic-pituitary-adrenal (HPA) axis so that plasma concentrations of ACTH and glucocorticoids are increased (Besedovsky et al, 1986;Dunn, 1988Dunn, ,2000. Furthermore, the peripheral sympathetic system is stimulated.…”

Microglial activation and TNFα production mediate altered CNS excitability following peripheral inflammation

“…1). Despite evidence that cytokines can directly influence synaptic function and neuronal properties in vitro (2-7) as well as alter transmitter biosynthetic pathways (1,8,9), the underlying mechanisms that link the peripheral inflammation, the central neuroimmune response, and CNS function are poorly understood.…”