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

`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 mu g/kg), IL-1 beta (15 or 50 mu g/kg), TNF-alpha (50 or 250 mu g/kg) or IL-6 (50 or 125 mu g/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-1 beta>TNF-alpha>>IL-6. Systemic LPS, IL-1 beta and TNF-alpha 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 IFN beta, which could only be induced by LPS. Systemic IL-1 beta could not induce significant blood TNF-alpha, but induced CNS TNF-alpha mRNA, while systemic TNF-alpha could induce IL-1 beta in blood and brain. Differences between IL-1 beta and TNF-alpha-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-1 beta and TNF-alpha both induced the chemokines CXCL1 and CCL2 but only IL-1 beta induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NF kappa B, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1 beta and to a lesser degree, TNF-alpha 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.