Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers.
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(+/+)) and IL-6 knock-out (IL-6(-/-)) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6(+/+) mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6(-/-) 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-1beta and tumor necrosis factor alpha (TNFalpha), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1beta and TNFalpha mRNA in neuronal layers of the hippocampus were determined in IL-6(+/+) and IL-6(-/-) mice after injection of LPS. Plasma IL-1beta and TNFalpha and c-Fos immunoreactivity in the NTS were increased similarly in IL-6(+/+) and IL-6(-/-) mice after LPS, indicating high circulating levels of IL-1beta and TNFalpha 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-1beta and TNFalpha mRNA that was evident in hippocampal tissue of IL-6(+/+) mice was greatly attenuated or entirely absent in IL-6(-/-) 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.
Sparkman
Nathan L
NL
Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA.
Buchanan
Jessica B
JB
Heyen
Jonathan R R
JR
Chen
Jing
J
Beverly
James L
JL
Johnson
Rodney W
RW
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D006624:Hippocampus / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides