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  • Review Article
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Interleukin-1 and neuronal injury

Nature Reviews Immunology volume 5, pages 629–640 (2005)Cite this article

Key Points

  • Interleukin-1 (IL-1) is a pro-inflammatory cytokine that mediates a diverse range of effects, in both the immune system and the central nervous system.

  • The tight regulatory control of the actions of IL-1 by several endogenous inhibitory molecules, including a receptor antagonist (IL-1RA), is an indicator of the biological importance of IL-1.

  • There is considerable experimental evidence supporting a role for IL-1 as a crucial mediator of neuronal injury in neurodegenerative disease. This includes both acute conditions, such as stroke and head injury, and chronic disorders, such as Alzheimer's disease and Parkinson's disease.

  • The mechanisms of IL-1 action in neuronal injury are not clearly defined and are the subject of intense research effort. There are discrepancies between in vitro and in vivo findings, and IL-1 seems to exert complex effects by influencing multiple cell types in the brain.

  • Clinical data also support a role for IL-1 in neurodegeneration. Consequently, a Phase IIa clinical trial involving IL-1RA treatment of patients who have suffered a stroke has just been completed.

  • Developing a greater understanding of the mechanisms of IL-1 action in neuronal injury, and developing interventions to target these effects, could lead to more effective treatments for stroke and other types of brain injury in the future.

Abstract

Interleukin-1 is a pro-inflammatory cytokine that has numerous biological effects, including activation of many inflammatory processes (through activation of T cells, for example), induction of expression of acute-phase proteins, an important function in neuroimmune responses and direct effects on the brain itself. There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders. This article discusses the key evidence of a role for interleukin-1 in acute neurodegeneration — for example, stroke and brain trauma — and provides a rationale for targeting the interleukin-1 system as a therapeutic strategy.

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Figure 1: The interleukin-1 family.
Figure 2: Regulation of interleukin-1β production and action.
Figure 3: Summary of proposed cellular actions of interleukin-1β in neuronal injury.
Figure 4: Therapeutic routes to targeting interleukin-1 in neurodegenerative disease.

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Author information

Authors and Affiliations

  1. Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK

    Stuart M. Allan & Nancy J. Rothwell

  2. Division of Neuroscience and Medicine, Hope Hospital, Salford, M6 8HD, UK

    Pippa J. Tyrrell

Authors
  1. Stuart M. Allan
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  2. Pippa J. Tyrrell
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  3. Nancy J. Rothwell
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Corresponding author

Correspondence to Stuart M. Allan.

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DATABASES

Entrez Gene

caspase-1

IL-1α

IL-1β

IL-1RA

IL-1RAcP

IL-1R1

IL-1R2

OMIM

Alzheimer's disease

FURTHER INFORMATION

Neurosciences at The University of Manchester

Glossary

ALZHEIMER'S DISEASE

A degenerative neurological disease that is characterized by progressive deterioration of the brain, dementia, and the presence of senile plaques, neurofibrillary tangles and neuropil threads. Disease onset can occur at any age, and women seem to be affected more frequently than men.

MICROGLIAL CELL

A macrophage-lineage cell that is derived from bone marrow and is present in the central nervous system.

ASTROCYTE

A type of glial cell that is found in vertebrate brain and is named for its characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, thereby regulating the environment in which neurons function.

ACUTE-PHASE PROTEIN

One of the group of proteins that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

EICOSANOID

A fatty-acid derivative. These molecules are mainly derived from arachidonic-acid precursors and have a wide variety of biological activities. There are four main classes of eicosanoid: prostaglandins, prostacyclins, thromboxanes and leukotrienes. They are derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.

CALPAIN

One of a group of calcium-activated cytoplasmic proteases that are found in many tissues and that hydrolyse various endogenous proteins, including neuropeptides and cytoskeletal proteins, as well as proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses are known: one with high calcium sensitivity, and one with low calcium sensitivity.

CASPASE

One of a group of enzymes that have a role in promoting apoptosis (that is, programmed cell death). Inhibition of such enzymes might be useful for combating cell and tissue damage in conditions such as myocardial infarction, stroke, inflammatory diseases and neurodegenerative disease. Augmentation of such enzymes, through the production of pro-apoptotic proteins, might be useful for combating proliferative conditions, such as cancer.

DECOY RECEPTOR

A receptor that can bind a ligand and thereby prevent the ligand from associating with the conventional signalling receptor.

TOLL/IL-1 RECEPTOR DOMAIN

(Toll/interleukin-1-receptor domain; TIR domain). An intracellular-signalling domain that is found in IL-1 receptors, Toll-like receptors and several adaptor proteins, including MyD88 (myeloid differentiation primary-response protein 88).

ISCHAEMIC INJURY

Damage to neurons that results from a deficiency in blood supply to that region of the brain, owing to functional constriction or physical obstruction of a blood vessel.

GLIAL CELL

A specialized cell that surrounds neurons. These cells provide mechanical and physical support for neurons and electrical insulation between neurons.

LONG-TERM POTENTIATION

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

SLOW-WAVE SLEEP

A phase of sleep in which there is slow oscillation of the eyes (also known as non-rapid-eye-movement sleep, non-REM sleep).

HYPOTHALAMIC–PITUITARY–ADRENAL AXIS (HPA axis).

An important part of the neuroendocrine system. It controls reactions to stress and involves the interactions of the hypothalamus, the pituitary gland and the adrenal glands.

NEUROTOXIC STIMULUS

A form of challenge that is damaging to neurons.

TRAUMATIC STIMULUS

A form of challenge that causes damage of a physical nature by accidental means and not through disease or illness.

EXCITOTOXIC STIMULUS

A challenge provided by excitotoxins: that is, glutamate or related compounds. Excessive exposure to this type of molecule results in the death of neurons, presumably through overstimulation.

INTRACEREBROVENTRICULAR

The administration of drugs or chemicals into the ventricular system of the brain. This route is often used in animal studies and is occasionally used in humans for the introduction of anti-infectives that do not penetrate the blood–brain barrier and therefore cannot usually enter the brain.

ORGANOTYPIC SLICE CULTURE

An in vitro preparation in which tissue from a particular brain region is cut into thin slices and maintained under culture conditions so that the architecture of the organ is preserved and all of the cell types are present.

OLIGODENDROCYTE

A type of glial cell that creates the myelin sheath that insulates axons and improves the speed and reliability of signal transmission by neurons.

MATRIX METALLOPROTEINASE (MMP).

An enzyme that degrades matrix proteins. In rheumatoid arthritis, MMP1 (also known as interstitial collagenase) can degrade type I collagen, and MMP3 (also known as stromelysin-1) can degrade proteoglycans.

MYELINATION

The formation of an insulating layer (that is, a myelin sheath) around a nerve fibre or axon to increase the speed at which action potentials are conducted.

INTRATHECAL

The administration of substances into the thin space between the lining of the spinal cord and the brain. This space contains cerebrospinal fluid.

SUBARACHNOID HAEMORRHAGE

An acute condition in which there is bleeding into the space between the meningeal layers (that is, the arachnoid membrane and the pia mater), which are adjacent to the brain.

MICRODIALYSIS

A technique for measuring the extracellular concentrations of substances in tissues, usually in vivo, using a small probe that is equipped with a semipermeable membrane. Substances can also be introduced into the extracellular fluid through the membrane of the probe.

PHASE IIa TRIAL

A pilot clinical trial to evaluate efficacy and safety in a relatively small number of patients who have the disease or condition to be treated, diagnosed or prevented. Such studies often involve hospitalized patients, because they can be closely monitored. The trial objectives might focus on dose–response, type of patient, frequency of dosing or several other issues that are involved in safety and efficacy.

C-REACTIVE PROTEIN

A protein that belongs to the pentraxin family. It is produced in the liver during inflammation.

BARTHEL INDEX AND MODIFIED RANKIN SCALE

Measures of a person's daily functioning and, more specifically, the ability to carry out the activities of daily living and the extent of mobility (Barthel Index) or disability (Modified Rankin Scale). These assessments are used to determine a baseline level of function after an individual has suffered a stroke, and they allow the monitoring of recovery over time.

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Allan, S., Tyrrell, P. & Rothwell, N. Interleukin-1 and neuronal injury. Nat Rev Immunol 5, 629–640 (2005). https://doi.org/10.1038/nri1664

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