A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1Β, TNF-α and IL-6 Challenges in C57BL/6 Mice

Abstract

It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful resource on the likely CNS inflammatory profiles resulting from systemic elevation of particular cytokines.

Nlrp-3-Driven Interleukin 17 Production by γδT Cells Controls Infection Outcomes during Staphylococcus aureus Surgical Site Infection

“…Quantitative PCR was performed on a CFX96 touch real-time PCR detection system (Bio-Rad) using the SsoFast probes supermix (BioRad) according to the manufacturer's recommendations. Quantitative PCR was performed using a primer/probe set designed to amplify PTX3 (forward, 5=-ACAACGAAATAGACAATGGACTTCAT-3=; reverse, 5=-C TGGCGGCAGTCGCA-3= probe, 5=-CCACCGAGGACCCCACGCC-3=; Sigma-Genosys) as previously described (37) and an 18S rRNA endogenous control (Life Technologies). Expression of PTX3 mRNA from S. aureus-infected wounds was compared to that of wounds from control mice treated with PBS by the change-in-cycle-threshold (⌬⌬C T ) method.…”

“…To further establish the differential in vivo effects on IL-1␤ signaling induced by these individual strains, we measured gene expression of pentraxin-related protein (PTX3) at the wound infection site. Expression of PTX3 has been shown to be induced during S. aureus infection (24), and importantly it appears that IL-1␤ is specifically responsible for its induction (37,40). Consequently, PTX3 has the potential to be used as a surrogate marker for assessment of IL-1␤ protein synthesis and bioactivitiy in vivo (37).…”

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

“…It is worth noting that in the stressful condition, microglial IL-6 expression is affected by treatment in an opposite fashion as compared to the expression of other pro-inflammatoryrelated genes. Previous studies have already found unique IL-6 expression profile compared to that of other pro-inflammatory cytokines in response to stressful (Audet et al, 2010) or immunogenic stimuli (Skelly et al, 2013). In addition, IL-6 has been reported to produce unexpected effects when used to modulate a variety of physiological processes, such as memory function (Arnold et al, 2002;Yirmiya and Goshen, 2011).…”

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

“…However, it is unclear if this lack of correlation between inflammatory markers was reflected centrally. Previous research has shown that relationship between TNF and other cytokines differ in the periphery and the CNS (Skelly et al, 2013). In addition, we restricted our analysis to those cytokines that have shown significant elevation in depressive illnesses.…”