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Cytokines and acute neurodegeneration

Key Points

  • Several cytokines are induced rapidly after acute brain injury. They are expressed in a temporal and spatial pattern that is consistent with their involvement in subsequent neuronal death.

  • Studies on the role of exogenous and endogenous cytokines in vivo and in vitro have yielded conflicting data. In general terms, interleukin 1 seems to contribute directly to neurodegeneration, whereas transforming growth factor-β is neuroprotective. Tumour necrosis factor-α can both enhance and inhibit neuronal injury; this dual action probably depends on the time course and level of its expression.

  • The complex actions and putative mechanisms of cytokines in the nervous system are similar to their functions in the periphery. Cytokines can act at very low concentrations on numerous cell types within or outside the brain. It is likely that the contribution of cytokines to neurodegeneration does not involve a single mechanism on one specific cell type, but rather depends on several actions, which might be detrimental or beneficial.

  • The primary mechanisms that regulate cytokine bioavailability, and the sites and mechanisms of action that result in neuronal death, have begun to be identified. Similarly, the pathways that transduce cytokine signalling and the interactions between these pathways are beginning to be understood. These insights will allow more effective interventions for the treatment of stroke and other types of brain injury.

Abstract

Cytokines have been implicated as mediators and inhibitors of diverse forms of neurodegeneration. They are induced in response to brain injury and have diverse actions that can cause, exacerbate, mediate and/or inhibit cellular injury and repair. Here we review evidence for the contribution of cytokines to acute neurodegeneration, focusing primarily on interleukin 1 (IL-1), tumour necrosis factor-α (TNFα) and transforming growth factor-β (TGFβ). TGFβ seems to exert primarily neuroprotective actions, whereas TNFα might contribute to neuronal injury and exert protective effects. IL-1 mediates ischaemic, excitotoxic and traumatic brain injury, probably through multiple actions on glia, neurons and the vasculature. Understanding cytokine action in acute neurodegeneration could lead to novel and effective therapeutic strategies, some of which are already in clinical trials.

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Figure 1: Damage after focal cerebral ischaemia.
Figure 2: Cytokine expression profile.
Figure 3: Signal transduction through IL-1RI and TNFR1.
Figure 4: Summary of putative actions of cytokines in neurodegeneration.

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Acknowledgements

This work was supported by the UK Medical Research Council. We thank Rosemary Gibson for helpful comments on the manuscript.

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Correspondence to Stuart M. Allan.

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DATABASES

LocusLink

BCL2

BCLX

caspase 1

COX2

FADD

FLIP

gp130

IKK

IL-1α

IL-1β

IL-1ra

IL-1RAcP

IL-1RAPL

IL-1RI

IL-6

IL-6R

IL-10

iNOS

intercellular cell-adhesion molecule 1

LTBP2

MyD88

P2X7 receptor

p53

PAI1

RIP1

TβR-I

TβR-II

TGFβ1

TLR4

TNFα

TNFR1

TNFR2

TRADD

FURTHER INFORMATION

Neuroimmunology Group Homepage

Glossary

CYTOKINES

In general terms, cytokines are proteins made by cells that affect the behaviour of other cells. They are produced mainly by the immune system.

MORBIDITY

The incidence or prevalence of a disease in a population.

ACUTE-PHASE PROTEINS

Molecules that are found in the blood shortly after an infection. They participate in early phases of host defence.

EICOSANOIDS

Polyunsaturated fatty acids that have widespread biological activities, such as muscle contraction, platelet aggregation and inflammation. Common examples include arachidonic acid, the leukotrienes and the prostanoids.

COMPLEMENT SYSTEM

A set of plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes.

INTERLEUKINS

A generic term for cytokines originally identified as products of leukocytes.

INTERFERONS

Cytokines that promote resistance to viral replication in cells.

CHEMOKINES

Small, secreted proteins that stimulate the motile behaviour of leukocytes.

CASPASES

Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.

NFκB

A heterodimeric transcription factor for eukaryotic RNA polymerase II promoters.

MITOGEN-ACTIVATED PROTEIN KINASE CASCADE

A signalling cascade that relays signals from the plasma membrane to the nucleus. MAPKs are activated by a wide range of proliferation- or differentiation-inducing signals.

FRACTALKINE

A membrane-bound chemokine that is highly expressed on activated endothelial cells, and is both an adhesion molecule and an attractant for T cells and monocytes.

RANTES

A chemokine that inhibits the infection of T cells by primary HIV-1 strains. RANTES stands for 'regulated upon activation, normal T-cell expressed, and presumably secreted'.

NEUROPOIETIC CYTOKINES

Cytokines that regulate cell number in the nervous system and might influence neuronal properties, such as the type of neurotransmitter used by certain neurons. They include ciliary neurotrophic factor and leukaemia-inhibitory factor.

IMMEDIATE-EARLY GENES

Genes that are expressed as one of the earliest responses of cells to factors that initiate the transition between the quiescent and activated states.

HEAT-SHOCK PROTEINS

Molecues that are synthesized in response to increased temperature. They function mainly as chaperones, protecting proteins as they become unfolded due to heating and enabling them to refold correctly.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

A rodent model of multiple sclerosis that is characterized by episodes of spasticity and tremor.

NEUROPROTECTIVE PRECONDITIONING

A phenomenon whereby a brief interruption of blood supply to the brain protects the tissue from a subsequent ischaemic episode.

SPREADING DEPRESSION

A slowly moving depression of electrical activity in the cerebral cortex. It consists of a wave of depolarization that can last for up to two minutes and travels at a speed between three and 12 millimeters per minute. Wave passage is accompanied by increased blood flow, and is followed by a prolonged period of vasodilation. Spreading depression seems to be related to migraine, and has been observed to accompany cerebral ischaemia.

PSD95

A protein of the postsynaptic density, which can interact with NMDA receptors. It is thought to participate in regulating the spatial distribution of this receptor subtype.

C-JUN N-TERMINAL KINASES

A family of kinases distantly related to extracellular-signal-regulated kinases (ERKs) that are activated by dual phosphorylation on tyrosine and threonine residues.

GLUCOCORTICOIDS

Hormones produced by the adrenal cortex, which are involved in carbohydrate and protein metabolism, but also affect brain function. Cortisol (human) and corticosterone (rodent) are prime examples.

CANNABINOIDS

Derivatives of 2-(2,2-isopropyl-5-methylphenyl)-5-pentyl-resorcinol, a molecule found in the plant Cannabis sativa. Cannabinoids are responsible for the psychoactive effects of marijuana.

LIPOPOLYSACCHARIDE

A toxic component of the outer cell wall of gram-negative bacteria.

CIRCUMVENTRICULAR ORGANS

Some of the structures located around the wall of the ventricular system, which are characterized by the absence of blood–brain barrier.

SMADS

A family of transcription factors that mediate TGFβ signals. The term SMAD is derived from the founding members of this family, the Drosophila αprotein MAD (mothers against decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size).

STATS

A family of cytoplasmic transcription factors (signal transducers and activators of transcription) that dimerize on phosphorylation and translocate to the nucleus to activate the transcription of target genes.

BCL PROTEINS

Molecules that are associated with B-cell leukaemia and lymphoma. BCL2 is a mitochondrial protein of the inner membrane, which can block apoptosis. BCLX is also a regulator of apoptosis, which exists in two forms: long and short.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of synaptic transmission, commonly elicited by high-frequency neuron stimulation.

FAS

A transmembrane protein that mediates apoptosis and might be involved in the negative selection of autoreactive T cells in the thymus.

VASOGENIC OEDEMA

The accumulation of extracellular fluid that results from changes in capillary permeability, allowing for the seepage of plasma molecules and water.

PYROGEN

Any agent capable of producing fever.

MULTIPLE SCLEROSIS

A neurodegenerative disorder characterized by demyelination of central nervous system tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.

SEPSIS

Infection of the soft tissues or blood by pathogens that results in tissue destruction.

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Allan, S., Rothwell, N. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2, 734–744 (2001). https://doi.org/10.1038/35094583

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