Cytokines and Sickness Behavior

Abstract

Peripheral and central injections of interleukin-1 (IL-1) and lipopolysaccharide (LPS) induce the expression of proinflammatory cytokines in the brain and have profound depressing effects on spontaneous and learned behaviors. These effects are mediated by vagal afferents, because they are abrogated by section of the vagus nerves at the subdiaphragmatic level in rats and mice. Vagotomy does not interfere with the synthesis and release of proinflammatory cytokines at the periphery, because plasma and tissue levels of interleukin-1 of vagotomized animals are similar to those of sham-operated animals. Furthermore, the consequences of vagotomy on the host behavioral response to peripheral cytokines are specific to the intraperitoneal route of administration of cytokines because vagotomized animals are still able to respond to IL-1 injected intravenously, subcutaneously, and into the lateral ventricle of the brain. Finally, substance P and cholecystokinin do not appear to play a key role in the transmission of the immune message to the brain because pretreatment by capsaicin or by specific antagonists of CCKA and CCKB receptors does not alter the behavioral effects of LPS and IL-1. All these findings point to the role of neural afferents for transmitting the immune message from the periphery to the brain.

Central LPS-Induced <i>c-fos</i> Expression in the PVN and the A1/A2 Brainstem Noradrenergic Cell Groups Is Altered by Adrenalectomy

“…Peripheral injections of LPS elevate c-fos mRNA levels in the A2 [51], the major site of vagal afferent termination. Recent experiments show that subdiaphragmatic vagotomy can partially suppress the elevations in ACTH [15], and CORT [16]which are seen following administration of a low dose of either IL-1 or LPS, and abolish sickness behavior [18]in addition to improving food-motivated behavior [17]. These data argue strongly for a major role for the vagus and hence these brainstem nuclei in mediating the central effects following peripheral immune activation.…”

“…Peripheral administration of LPS leading to activation of brainstem noradrenergic cell groups has been shown to involve the activation of vagal afferents as vagotomy has been demonstrated to suppress LPS-induced neuronal activation within the nucleus tractus solitarius (NTS) [15], in addition to reducing IL-1β-induced elevations in plasma CORT [16], altering food-motivated behavior in mice [17], and reducing sickness behavior [18]. Although the results of peripheral administration of LPS and the subsequent activation of central systems have been well investigated and have been shown to activate the HPA axis, the effects of central administration of LPS to determine signalling within the brain are as yet still under investigation.…”

Neuroimmune Activation Drives Multiple Brain States

“…In general, neuroimmune activation is commonly defined by behavioral changes, by the activation of microglia, or by increased level or expression of immune molecules, in particular cytokines and chemokines (Dantzer et al, 1998; McCusker and Kelley, 2013; del Rey et al, 2013; Becher et al, 2017). Behavioral changes, notably sickness behaviors and associated febrile response and weight loss, are commonly used to assess immune (and neuroimmune) activation.…”

“…That the activation of the neuroimmune system drives a unique brain and behavioral state is clear from the distinct consequences of illness on behavior, cognition, emotion and learning and memory (Dantzer et al, 1998; Yirmiya and Goshen, 2011; Donzis and Tronson, 2014). The roles of cytokines and immune molecules in the modulation of memory has been a particular point of recent interest (Pugh et al, 1998; Marin and Kipnis, 2013; del Rey et al, 2013).…”

The Etiology and management of radiotherapy-induced fatigue

“…The inflammatory cytokines (e.g. IL-1, IL-6, TNF-α) from these cells are thought to communicate with CNS structures causing fatigue by altering neurotransmission in the CNS through the afferent vagus nerve root [32]. For example, the neurons of the preoptic nucleus that synthesize IL-1β have processes that have ramifications for other CNS structures, including the limbic system and the brainstem causing modulation of the neural response leading to significant fatigue [31].…”