Pro-inflammatory cytokines and their effects in the dentate gyrus

doi:10.1016/S0079-6123(07)63020-9

Progress in Brain Research

Volume 163, 2007, Pages 339-354

https://doi.org/10.1016/S0079-6123(07)63020-9 Get rights and content

Abstract

The older notion of a central nervous system existing in essential isolation from the immune system has changed dramatically in recent years as the body of evidence relating to the interactions between these two systems has grown. Here we address the role of a particular subset of immune modulatory molecules, the pro-inflammatory cytokines, in regulating neuronal function and viability in the dentate gyrus of the hippocampus. These inflammatory mediators are known to be elevated in many neuropathological conditions, such as Alzheimer's disease, Parkinson's disease and ischaemic injury that follows stroke. Pro-inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin 1-β (IL-1β) and interleukin 18 (IL-18), have been shown to regulate neurotoxicity; although, due to the complexity of the cytokine action in neurons and glia, the effect may be either facilitatory or protective, depending on the circumstances. As well as their role in neurotoxicity and neuroprotection, the pro-inflammatory cytokines have also been shown to be potent regulators of synaptic function. In particular, TNF-α, IL-1β and IL-18 have all been shown to inhibit long-term potentiation, a form of neuronal plasticity widely believed to underlie learning and memory, both in the early p38 mitogen activated protein kinase-dependant phase and the later protein synthesis-dependant phase. In this article we address the mechanisms underlying these cytokine effects in the dentate gyrus of the hippocampus.

Introduction

The older notion of two “super-systems”, nervous and immune, existing in relative isolation from each other due largely to the blood-brain barrier, has given way in recent years to a new consensus, as it became apparent that many immune molecules may be used by the nervous system in intercellular communication (Boulanger et al., 2001; Chun, 2001). Chief amongst these are the cytokines — multifunctional proteins that play crucial roles in cellular communication and activation. Cytokines have been classified as pro-inflammatory or anti-inflammatory depending on the balance of their effects on the immune system (Mosmann et al., 1986). Cytokines may have an indirect modulatory effect on the nervous system via their effects on the hypothalamic-pituitary-adrenal axis (Besedovsky et al., 1991). However, here we will address the direct effect roles of the pro-inflammatory cytokines, in particular tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-18 (IL-18) on the CNS in general, and the dentate gyrus in particular.

Section snippets

Distribution of pro-inflammatory cytokines in the CNS

Direct action of the pro-inflammatory cytokines TNF-α and IL-1β on the CNS has been known for some time (Plata-Salaman et al., 1988). Elevated CNS expression of various pro-inflammatory cytokines have been noted in many neuropathological situations, both chronic, such as Alzheimer's disease (Cacquevel et al., 2004) and multiple sclerosis (Merrill, 1992), and acute, such as ischemia and stroke (Liu et al., 1994; Klein et al., 2000; Yu and Lau, 2000), and infection (Waage et al., 1989).

Action of TNF-α in the dentate gyrus

The pro-inflammatory cytokine TNF-α is a 17-kDa peptide and forms multimers which are active in binding TNF receptors (TNFR) that are constitutively expressed on both neurons and glia in the central nervous system (Benveniste and Benos, 1995). TNF-α can be synthesized and released in the brain by astrocytes, microglial and some neurons (Lieberman et al., 1989; Morganti-Kossman et al., 1997; Chung and Benveniste, 1990). Under various pathological conditions, such as trauma, ischemia and

Role of TNF-α in excitotoxicity

Excitotoxicity in general is linked to excessive glutamate activation of receptors, particularly the N-methyl-d-aspartate (NMDA) receptor. Cell death resulting from excessive levels of glutamate and overstimulation of glutamate receptors is known to be caused by impaired uptake of glutamate by glial cells (Choi, 1988). In vivo, it has been shown that mice lacking expression of the excitatory amino-acid transporter, EAAT2/GLT-1, develop epilepsy and increased susceptibility to acute injury as a

TNF-α and synaptic transmission

The subject of TNF-α in glial–neuronal interactions also emerges when looking at synaptic transmission. Beattie et al. (2002) showed that glial TNF-α causes an increase in surface expression of neuronal AMPA receptors, which would increase synaptic efficacy, and that the removal of endogenous TNF-α induced a decrease in AMPA receptor expression at the cell surface. Further evidence for this relationship between TNF-α and AMPA receptor density came from Stellwagen and Malenka (2006), who found

TNF-α and synaptic plasticity

Changes in neuronal excitability brought about by TNF-α have important implications for synaptic plasticity (Carroll et al., 2001). Indeed, TNF-α is known to act as a regulator of synaptic plasticity in the dentate gyrus, in addition to playing a role in apoptotic events. As previously mentioned, elevated levels of TNF-α have been observed in several neuropathological states that are associated with learning and memory deficits, such as Alzheimer's disease, leading to the search for a possible

IL-1β receptors

As described for TNF-α, IL-1 receptors have also been shown to be present in many brain regions, with high levels in the hippocampus and hypothalamus (Ban et al., 1991). There are a number of receptors to which IL-1 can bind (O’Neill, 1997). The principal mediator of IL-1 signalling in the CNS is believed to be the type I IL-1 receptor (IL-1R1), which initiates intracellular events upon IL-1β binding (O’Neill, 1996), although the type II IL-1 receptor (IL-1R2) is also present, which although

Concluding remarks

The overriding theme among studies of pro-inflammatory cytokines in the dentate gyrus, and other brain regions, is that of complexity. A primary example is the potential for opposing actions. In addition, the action of these cytokines on neurons is often subtle and multi-faceted, with very different short- and long-term consequences, making their elucidation all the more challenging. A more comprehensive understanding cannot be achieved until the interactions between the cytokine receptors and

Acknowledgements

We would like to thank the Health Education Authority, Ireland, PRTLI Cycle 3 for funding and Dr Derval Cumiskey for assistance on figure production.

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Pro-inflammatory cytokines and their effects in the dentate gyrus

Abstract

Introduction

Section snippets

Distribution of pro-inflammatory cytokines in the CNS

Action of TNF-α in the dentate gyrus

Role of TNF-α in excitotoxicity

TNF-α and synaptic transmission

TNF-α and synaptic plasticity

IL-1β receptors

Concluding remarks

Acknowledgements

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Curr. Opin. Neurobiol.

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Neuron

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Eur. J. Pharmacol.

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Neurosci. Lett.

Neuroscience

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Brain Res. Mol. Brain Res.

Exp. Neurol.

Cell

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Trends Cell Biol.

Brain Res.

Biochem. Biophys. Res. Commun.

Neurochem. Int.

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Prog. Neurobiol.

Neuropharmacology

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Cell

Neurobiol. Ageing

Trends Neurosci.

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Adv. Immunol.

J. Biol. Chem.

Mol. Brain Res.

Cell

Brain Res. Bull.

Eur. J. Pharmacol.

Brain Res.

Trends Neurosci.

Evidence for the involvement of TNF-α and NF-kappaB in hippocampal synaptic plasticity

Synapse

Cytokines and acute neurodegeneration

Nat. Rev. Neurosci.

Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity

Hippocampus

Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation

Proc. Natl. Acad. Sci. U.S.A.

A newly defined interleukin-1b

Nature

Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca²⁺ accumulation