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Title: Interleukin-6 trans-signaling: implications for neuroinflammation and cognitive deficits in the aged
Author(s): Burton, Michael
Director of Research: Johnson, Rodney W.
Doctoral Committee Chair(s): Johnson, Rodney W.
Doctoral Committee Member(s): Freund, Gregory G.; Woods, Jeffrey A.; Dilger, Ryan N.
Department / Program: Animal Sciences
Discipline: Animal Sciences
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Interleukin-6
trans-signaling
aging
sickness behavior
cognition
learning and memory
pro-inflammatory
microglia
neuron
Abstract: In the event of peripheral infection, aged mice exhibit a heightened central inflammatory cytokine response, as well as prolonged behavioral and cognitive deficits when compared to adults. This is attributed to a population of activated or “primed” microglia that produce excessive amounts of pro-inflammatory cytokines, such as interleukin (IL)-6. The over production of IL-6 during aging is correlated with acute behavioral deficits in response to a peripheral infection or chronic behavioral deficits in the development of neurodegenerative diseases, such as Alzheimer’s and Multiple Sclerosis . However IL-6 is implicated in pro- and anti-inflammatory processes, so it is vital to understand it’s mechanisms in aging, neuroinflammation, and neurodegeneration. In initial studies using a microglia cell line (BV.2), we found that the IL-6 trans-signaling pathway stimulated MHC-II, a marker of activation. While microglia isolated from aged IL-6 knock-out animals displayed significantly less MHC-II expression. Additionally, IL-6 knock-out animals were refractory to LPS-induced sickness behavior implicating the involvement of IL-6 and microglial activation in aging. However, which arm of IL-6 signaling had the most influential effects remained unclear. Recently, IL-6 trans-signaling has been shown to induce the pro-inflammatory actions of IL-6 and selective blockade of the trans-signaling cascade using soluble gp130 (sgp130) has reduced the deleterious effects of peripheral inflammatory conditions such as Crohn’s disease and arthritis. Although sgp130 has been shown to inhibit peripheral inflammation, its effects on the inflammatory response in the brain are unknown. If sgp130 reduces inflammation in the brain, it is rational to hypothesize that it will protect aged animals from infection-related exaggerated levels of IL-6 and behavioral deficits. In a series of studies testing this hypothesis, sgp130 was found to inhibit LPS-induced IL-6 production via STAT3-dependent action in BV.2 cells. In subsequent studies, adult and aged mice were co-administered vehicle or sgp130 via intracerebroventricular (icv) and i.p. with saline or LPS. As expected, aged mice displayed deficits in locomotor activity and hippocampal-dependent memory tasks, indicating they were more sensitive to peripheral immune stimulation. Importantly, LPS-induced sickness behavior and cognitive deficits in aged animals were mitigated by icv sgp130. These behavioral effects were mirrored by a reduction of STAT3 phosphorylation, IL-6 mRNA expression, and protein production in hippocampal tissue. Additionally, sgp130 also attenuated the induction of IL-6 protein from isolated microglia and astrocytes from the aged. These data show that inhibiting the IL-6 trans-signal, suggests a possible role in attenuating acute cognitive and behavioral disorders in older individuals with an infection.
Issue Date: 2012-09-18
URI: http://hdl.handle.net/2142/34254
Rights Information: Copyright Clearance Center RightsLink (Elsevier) 2012
Date Available in IDEALS: 2012-09-18
Date Deposited: 2012-08


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