Inactivation of the Cerebral NFκB Pathway Inhibits Interleukin-1β-Induced Sickness Behavior and c-Fos Expression in Various Brain Nuclei

Abstract

The behavioral effects of peripherally administered interleukin-1b (IL-1b) are mediated by the production of cytokines and other proinflammatory mediators at the level of the blood-brain interface and by activation of neural pathway. To assess whether this action is mediated by NFkB activation, rats were injected into the lateral ventricle of the brain with a specific inhibitor of NFkB activation, the NEMO Binding Domain (NBD) peptide that has been shown previously to abolish completely IL-1b-induced NFkB activation and Cox-2 synthesis in the brain microvasculature. NFkB pathway inactivation significantly blocked the behavioral effects of intraperitoneally administered IL-1b in the form of social withdrawal and decreased food intake, and dramatically reduced IL-1b-induced c-Fos expression in various brain regions as paraventricular nucleus, supraoptic nucleus, and lateral part of the central amygdala. These findings strongly support the hypothesis that IL-1b-induced NFkB activation at the blood-brain interface is a crucial step in the transmission of immune signals from the periphery to the brain that underlies further events responsible of sickness behavior.

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

“…Firstly, the SERT gene promoter is known to contain a consensus NF-jB binding site, suggesting that this transcription factor may be involved in the regulation of SERT gene expression in response to inflammatory stimulation [49]. Also, this transcription factor has previously been implicated in the precipitation of the clinical manifestation of sickness behavior as blockade of NF-jB activation following peripheral administration of IL-1b has been shown to attenuate the depressive-like behavioral effects of this peripherally administered cytokine in experimental animals [50]. Finally, the stimulation of both, primary astrocytes and C6 glioma cells, with TNF-a results in the activation of the NF-jB signaling pathway [40,51,52].…”

“…1b). Using 50nM [ 3 H]5-HT, we obtained average IC 50 values for three well characterized SERT inhibitors: paroxetine, 0.66 ± 0.14 nM; escitalopram, 1.2 ± 0.35 nM; imipramine, 35.4 ± 1.6 nM. These values as well as the order of potency of these inhibitors, i.e.…”

Signals generating anorexia during acute illness

“…The absence of MyD88 signalling has recently been shown to completely eliminate anorexia in response to either LPS or IL-1b . Interference with NF-kB production has also been shown to block the feeding-inhibitory effect of IL-1b (Nadjar et al 2005) and is the most likely mechanism by which genetic lack of PPARb, administration of phosphodiesterase inhibitors such as pentoxifylline (Porter et al 2000) and some other pharmacological interventions antagonize the feeding-inhibitory effect of LPS (for review, see Langhans, 2004). The neural mechanism(s) that mediate these effects, however, have not yet been determined.…”

Identification and treatment of symptoms associated with inflammation in medically ill patients

“…Michael May (Philadelphia, Pennsylvania) reported on the ability to specifically block the activation of this pathway upstream of NFκB activation, at the level of the IκB-kinase complex, using an inhibitor of the regulatory protein NEMO (NFκB essential modifier) coupled to a cell permeable peptide (May et al, 2000). Such blockade abrogates inflammation in various in vivo animal models, including cytokine-induced sickness behavior (Nadjar et al, 2005). Activation of stress-activated protein/mitogenactivated protein kinase (SAPK/MAPK) pathways also plays an important role in inflammation.…”