New roles for interleukin-1 Beta in the mechanisms of epilepsy

Abstract

The mechanisms that transform a normal brain to an epileptic one are not fully understood. Interleukin-1 beta (IL-1beta) contributes to neuronal degeneration observed in several neurological disorders and recently has been implicated in neuronal injury that may accompany the process of epileptogenesis. This review presents the hypothesis that IL-1beta may contribute to the development of epilepsy via several mechanisms, including classical effects on neuronal survival and transcription pathways; novel rapid effects on receptor-gated ion channels; and long-lasting effects on expression of selective gene families. Thus, evidence that IL-1beta actions in epilepsy can be independent from the neurotoxic effects of this cytokine is presented.

FIGURE 1

IL-1β and Epileptogenesis. This schema depicts the cascade of events that may underlie CNS actions of IL-1β after its production and release following a precipitating event. Brain IL-1β is mainly produced by glia (microglia and astrocytes); endothelial cells of the blood–brain barrier, neurons, and lymphocytes represent additional sources. Since the same cells that produce IL-1β also express IL-1 type 1 receptors (IL-1R1), it appears that this cytokine is endowed with both autocrine and paracrine actions. Activation of IL-1R1 by IL-1β can trigger rapid effects on neuronal excitability, leading to rapid ion channel changes mediated by activation of kinases, such as Src and phosphoinositol 3 kinase (PI3K) (19,20,23). These actions are likely to be responsible for the proconvulsive actions of IL-1β and may contribute to seizure-associated neuronal death. Long-term effects also may be triggered by IL-1β via transcriptional activation of NF-κB- and MAPK-dependent genes involved in structural and functional changes in glial and neuronal networks. These actions, individually or in concert, may contribute to epileptogenesis. However, available experimental evidence indicates that induction of neuronal cell death does not appear to be a prerequisite for the pro-epileptogenic actions of IL-1β.