Interleukin-6 Facilitates Lipopolysaccharide-Induced Disruption in Working Memory and Expression of Other Proinflammatory Cytokines in Hippocampal Neuronal Cell Layers

Abstract

Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6 ϩ/ϩ ) and IL-6 knock-out (IL-6 Ϫ/Ϫ ) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6 ϩ/ϩ mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6 Ϫ/Ϫ mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1␤ and tumor necrosis factor ␣ (TNF␣), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1␤ and TNF␣ mRNA in neuronal layers of the hippocampus were determined in IL-6 ϩ/ϩ and IL-6 Ϫ/Ϫ mice after injection of LPS. Plasma IL-1␤ and TNF␣ and c-Fos immunoreactivity in the NTS were increased similarly in IL-6 ϩ/ϩ and IL-6 Ϫ/Ϫ mice after LPS, indicating high circulating levels of IL-1␤ and TNF␣ and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1␤ and TNF␣ mRNA that was evident in hippocampal tissue of IL-6 ϩ/ϩ mice was greatly attenuated or entirely absent in IL-6 Ϫ/Ϫ mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.

SIGIRR modulates the inflammatory response in the brain

“…We report that SIGIRR -/-mice have increased expression of the microglial markers CD40 and ICAM in response to LPS compared to wildtype mice; the co-stimulatory molecules CD80 and CD86 were also upregulated SIGIRR -/-mice in response to LPS and this effect was not observed in wildtype mice. As previously reported, LPS increased IL-6 and TNFα at mRNA and protein levels in hippocampus (Chen et al, 2008;Hellstrom et al, 2005;Loane et al, 2007;Sparkman et al, 2006); significantly, and in parallel with the changes in vitro, the effect of LPS was markedly greater in hippocampus of SIGIRR -/-mice.…”

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

“…These results are noteworthy because IL-6 in the periphery plays a role in the pathogenesis of immunologically mediated fatigue and loss of strength (33,34). Furthermore, the hippocampus is densely populated with microglia, and inflammatory cytokines are well known to inhibit working memory (35) and memory consolidation (36) in hippocampaldependent tasks. Although flavonoids can penetrate the bloodbrain barrier (37), it is unclear whether luteolin entered the brain to directly inhibit IL-6 expression or whether it reduced hippocampal IL-6 indirectly by reducing peripheral responses to LPS.…”

Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults

“…Animal models show that peripheral inflammation stimulates the production of IL-6 by activated mononuclear and glial cells in the hippocampus (e.g., 8), which, in turn, inhibits neurogenesis, decreases synaptic plasticity, and disrupts learning and memory (12,14,15,18,20,43). It is feasible that this pathway accounts for the observed anatomically-specific relationship between higher peripheral IL-6 and lower hippocampal grey matter volume, which may reflect a possible structural neural correlate of inflammation-related cognitive decline.…”

“…Conversely, IL-6 receptor antagonists prevent inflammation-related disruption of hippocampal LTP and ensuing cognitive sequelae (18). Finally, IL-6 knockout mice show facilitated working memory when compared with wild type mice (19) and are refractory to peripheral endotoxin-induced impairments of spatial memory (20). Together, these animal findings suggest that higher peripheral IL-6 is associated with hippocampal inflammatory mechanisms that negatively affect cognitive processes, including memory and learning.…”