Cytokines and brain excitability

doi:10.1016/j.yfrne.2011.12.002

Frontiers in Neuroendocrinology

Volume 33, Issue 1, January 2012, Pages 116-125

https://doi.org/10.1016/j.yfrne.2011.12.002 Get rights and content

Abstract

Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission.

Highlights

► Cytokines are produced in brain in response to a peripheral or brain inflammation. ► Cytokines are also produced during seizure activity. ► Cytokines augment seizure activity and may be important in epileptogenesis. ► Cytokines upregulate glutamatergic and downregulate GABAergic synapses.

Section snippets

Introduction to cytokines

Cytokines are signaling proteins secreted primarily by cells of the immune system, including monocytes, macrophages (e.g. Kupffer cells, microglia), lymphocytes (B and T cells), and vascular endothelial cells that signal the detection of pathogens and activate cellular networks to initiate the appropriate immunological responses. There are many classes of cytokines including numerous interleukins, lymphokines, chemokines, hematopoietins, interferons, as well as members of the platelet derived

Inflammatory models and cytokine production

Cytokine blood levels are normally low, but they can markedly increase in response to pathogens, inflammation, or tissue injury, as well as in a variety of disease processes like autoimmunity and cancer. Since the inflammatory cascade in many of these entities is difficult to control in an experimental setting, one common method of inducing a predictable course of inflammation in the laboratory is by using lipopolysaccharide (LPS), the pyrogenic component of the outer membrane of gram negative

Peripheral inflammatory signaling to the brain

Detection of a peripheral immune response occurs via vagal afferents, circumventricular organs, and directly at the blood brain barrier (BBB) [13]. For most systemic inflammatory responses, signaling at the BBB appears to be the dominant means by which the brain responds to peripheral signals; endothelial and perivascular cells synthesize prostaglandin E₂ [59], [138], [144] which diffuses into the parenchyma to stimulate heat conservation and production pathways in the hypothalamus and cause

Cytokines, seizures and epilepsy

The evidence is now overwhelming that epilepsy is associated with inflammation and with elevated levels of cytokines. Virtually all of the pro-inflammatory cytokines are elevated in tissue or cerebral spinal fluid (CSF) from patients with chronic seizure disorders (rev. in [4]). For example, some types of medically intractable epilepsy arising from focal cortical malformations are associated with both increased gene expression [15] and elevated levels of pro-inflammatory cytokines in the CNS

Cellular and molecular effects of cytokines on neuronal excitability

Because of the widespread actions of cytokines in the brain, there have been intensive electrophysiological and pharmacological investigations of their cellular actions over the past 20 years. While this review will focus upon cytokine actions on neuronal excitability, it is important to note that cytokine receptors exist on non- neuronal cells as well. Thus there have been extensive investigations of their electrophysiological effects upon microglia [141] as well as studies of their effects

Conclusion and perspectives

The functional diversity of cytokines has far surpassed their limited role as simple immune system messengers. Like other passing dogmas in Neuroimmunology, such as the view that the brain is an immune privileged site, the role of cytokines in physiological and pathological activity of the brain has expanded. However, the important consideration is how to harness this knowledge and funnel it towards alleviation or treatment of neurological disorders such as epilepsy. In this regard, it is

Acknowledgments

This work was supported by the Canadian Institutes of Health Research, the Crohn’s and Colitis Foundation of Canada Chair in IBD Research and the Natural Sciences and Engineering Research Council of Canada and by personnel support grants from the Alberta Heritage Foundation for Medical Research and the Savoy Foundation.

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ReviewCytokines and brain excitability

Abstract

Highlights

Section snippets

Introduction to cytokines

Inflammatory models and cytokine production

Peripheral inflammatory signaling to the brain

Cytokines, seizures and epilepsy

Cellular and molecular effects of cytokines on neuronal excitability

Conclusion and perspectives

Acknowledgments

IL-1beta is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence

Neurobiol. Dis.

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

Synapse

Interleukin-1 and neuronal injury

Nat. Rev. Immunol.

Inflammation in epilepsy: clinical observations

Epilepsia

Inflammation enhances epileptogenesis in the developing rat brain

Neurobiol. Dis.

Inflammation exacerbates seizure-induced injury in the immature brain

Epilepsia

Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA

Epilepsia

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-kappaB in hippocampal neuronal cell culture

J. Neuroimmunol.

A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta

Brain

Control of synaptic strength by glial TNFalpha

Science

AMPA-receptor trafficking and injury-induced cell death

Eur. J. Neurosci.

Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus

Brain Res.

The onset of fever: new insights into its mechanism

Synergy between tumor necrosis factor a and interleukin-1 in the induction of sickness behaviour in mice

Psychoneuroendocrinology

Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors

Brain Pathol.

Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex

Epilepsy Res.

Immune proteins in brain development and synaptic plasticity

Neuron

Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration

Proc. Natl. Acad. Sci. USA

Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures

Neurobiol. Dis.

Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets

Neurochem. Int.

Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells

Neuroscience

Transgenic models to study the actions of cytokines in the central nervous system

Neuroimmunomodulation

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NeuroReport

Endogenous interleukin-10 is required for the defervescence of fever evoked by local lipopolysaccharide-induced and Staphylococcus aureus-induced inflammation in rats

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The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

Cell Death. Differ.

Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines

J. Neurosci.

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling

Proc. Natl. Acad. Sci. USA

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

J. Neuroimmunol.

Cellular injury and neuroinflammation in children with chronic intractable epilepsy

J. Neuroinflammation

Cytokines and fever

Front Biosci.

Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation

J. Neurosci.

Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus

Eur. J. Neurosci.

Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation

Brain Behav. Immun.

Interleukin 1beta modulates rat subfornical organ neurons as a result of activation of a non-selective cationic conductance

J. Physiol.

Prolonged inflammatory gene response following soman-induced seizures in mice

Toxicology

Review
Cytokines and brain excitability