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The neuropoietic cytokine family in development, plasticity, disease and injury

Key Points

  • Neuropoietic cytokines have a crucial role in nervous system development. Leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) have historically been associated with the development of astrocytes from neural stem and progenitor cells. With the discovery that some astrocytes are neurogenic, the potential of these cytokines to promote the development of astrocytes versus neural stem cells is being re-investigated.

  • Cardiotrophin 1, but not LIF or CNTF, is involved in the temporal switch from neurogenesis to gliogenesis during nervous system development.

  • Exogenous LIF stimulates mouse embryonic stem cell self-renewal in vitro, and adult neural stem cell self-renewal in vivo in the uninjured brain.

  • Because endogenous LIF is transiently induced after many types of injury to the nervous system, LIF might be involved in progenitor cell recruitment after brain injury and could be used to promote brain repair.

  • Neuropoietic cytokines are crucial in the response to injury. In certain settings they can act as trophic factors promoting survival and regeneration of injured axons. However, they are also intimately linked with inflammatory responses and reactive gliosis after injury, which can have negative consequences for neuronal survival and axon regeneration.

  • While these cytokines might prove to be effective therapeutic tools to promote neuronal and oligodendrocyte survival in CNS diseases such as amyotrophic lateral sclerosis and multiple sclerosis, their ability to stimulate inflammatory and glial responses must be carefully monitored in order to limit unwanted side effects.

  • IL-6 is implicated in long-term potentiation. These effects could occur through direct effects of interleukin-6 (IL-6) on neuronal excitability and through the regulation of Ca2+ influx. A role for IL-6 in learning and memory is supported by cognitive tests.

  • In animal models, LIF modulates the hypothalamic–pituitary–adrenal axis response to stress, and both LIF and IL-6 induce depression-like behaviours. In humans, IL-6 could have a role in symptoms of fatigue, asthenia and anorexia in major depression and bipolar disorder.

  • LIF, CNTF and IL-6 are involved in feeding behaviour and control of body weight. There are also indications that members of this cytokine family can regulate sleep, motor activity patterns, aggression and social interaction.

Abstract

Neuropoietic cytokines are well known for their role in the control of neuronal, glial and immune responses to injury or disease. Since this discovery, it has emerged that several of these proteins are also involved in nervous system development, in particular in the regulation of neurogenesis and stem cell fate. Recent data indicate that these proteins have yet more functions, as key modulators of synaptic plasticity and of various behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of psychiatric disorders.

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Figure 1: Neuropoietic cytokine receptor complexes.
Figure 2: LIF and CNTF regulation of stem cells: from totipotent embryonic stem cells to adult neural stem cells.
Figure 3: LIF mediates injury responses in the PNS.
Figure 4: Neuropoietic cytokines promote motor neuron and oligodendrocyte survival after injury or disease.

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Acknowledgements

We thank K. Hamilton for help in preparing the manuscript, and D. McDowell and B. Lease for administrative support on the work done in the Patterson laboratory. Our research discussed here was supported by grants from the National Institute of Neurological Disease and Stroke, the John Douglas French Alzheimer's Foundation, the McGrath Foundation, a Cline Neuroscience Discovery Grant, and the Roman Reed Spinal Cord Injury Research Fund of California.

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DATABASES

OMIM

amyotrophic lateral sclerosis

Huntington's disease

multiple sclerosis

schizophrenia

Glossary

Stem cell self-renewal

A characteristic of stem cells, which divide asymmetrically to give rise to a new stem cell (self-renewal) and a more differentiated progenitor cell. Tissue stem cells can thereby persist in the long term and ensure a continuous supply of more differentiated progenitors.

Embryonic stem cell

(ESC). A particular type of stem cell that is derived in vitro from the inner cell mass of the early embryo at the blastocyst stage. ESCs are totipotent, that is, they can give rise to any differentiated cell type.

Neural stem cell

(NSC). A self-renewing stem cell of the neural lineage, that is, it can give rise to neurons, astrocytes and oligodendrocytes.

Replicative senescence

Stage at which cells maintained in vitro cease proliferation and cannot be passaged further.

Neural progenitor cell

Dividing cell that has a limited proliferating and self-renewing capacity, and is restricted to the neural lineage.

Subventricular zone

(SVZ). Area lining the lateral ventricle, which contains neural stem and progenitor cells that give rise to new neurons in the olfactory bulb of the adult brain.

Autoregenerative factor

Factor synthesized by a population of degenerating cells that promotes the regeneration of the same cell type.

Gliosis

The process of producing a dense fibrous network of neuroglia; includes astrocytosis — the proliferation of astrocytes in the area of a degenerative lesion.

Mechanical allodynia

Pain caused by a mechanical stimulus that is normally perceived as non-painful.

Thermal hyperalgesia

An increased sensitivity to a painful thermal stimulus.

Neuropathic pain

Pain initiated or caused by a primary lesion or dysfunction of the nervous system.

C-fibre

The small diameter, unmyelinated axons of sensory neurons that convey information about potentially tissue-damaging stimuli.

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Bauer, S., Kerr, B. & Patterson, P. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 8, 221–232 (2007). https://doi.org/10.1038/nrn2054

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