Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration

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Abstract

Experimental studies suggest that cytokine production may be triggered by seizure activity. Here we determined the levels of interleukin-6 (IL-6) and its soluble receptor components (sIL-6R and sGp130) in CSF and serum from control subjects and patients after different types of seizures. IL-6 levels were increased after seizures, whereas sIL-6R levels were decreased. Interestingly, the levels of IL-6 were strongly increased after recurrent generalized tonic-clonic seizures (GTCS), whereas after single tonic-clonic or prolonged partial seizures IL-6 levels were increased to lesser extent. These results provide further support for a hypothesis of cytokine production induced by seizure activity per se.

Introduction

In the central nervous system (CNS), cytokines are produced as a response to various inflammatory stimuli. Recently, experimental studies have revealed that cytokine production may be induced also by seizure activity Jankowsky et al., 2000, Vezzani et al., 1999. Interestingly, modulation of cytokine network has been shown to affect duration and spread of seizure activity D'Arcangelo et al., 2000, De Simoni et al., 2000, Vezzani et al., 1999, as well as seizure susceptibility (Vezzani et al., 2000). In addition, seizure-induced production of cytokines may contribute to formation of structural changes after sustained seizure activity, such as neuronal damage and gliosis Panegyres and Hughes, 1998, Penkowa et al., 2001.

Interleukin-6 (IL-6) is a cytokine with multiple effects on various cell types and tissues throughout the body. In the CNS, IL-6 has been revealed to have both neuroprotective Penkowa et al., 2001, Penkowa et al., 2003 and neurotoxic effects (Campbell et al., 1993). IL-6 receptor complex has two components, interleukin-6 receptor (IL-6R) and glycoprotein 130 (Gp130), both of which are also released in soluble forms. Soluble IL-6R (sIL-6R) has mainly agonistic effects on IL-6 signalling (Peters et al., 1996), whereas soluble Gp130 (sGp130) acts as an antagonist Muller-Newen et al., 1998, Jostock et al., 2001. Due to the modulating role of these soluble receptors, the levels of these receptor components should be evaluated in order to assess IL-6 activity.

In our previous studies Peltola et al., 1998, Peltola et al., 2000a, increased levels of IL-6 were measured in CSF and plasma of patients with recent generalized tonic-clonic seizures (GTCS). Only patients with single GTCS were included in these studies. However, whether this observed increase in IL-6 levels is related directly to the seizure activity or some other seizure-related phenomenon is not fully understood. In the present study, we examined patients with different seizure patterns in order to evaluate the effect of seizure activity per se on IL-6 system.

Section snippets

Patients and methods

Thirty-three consecutive patients coming to the emergency department of Tampere University Hospital with acute seizures were included in the study. Patients with any signs of inflammatory or infectious disease were excluded from the study. Three groups of patients were examined in this study. The first patient group consisted of 16 patients with single GTCS. The second group included 10 patients with recurrent GTCS, who had experienced two or more recurrent GTCS before admission to the

Levels of IL-6 in CSF and serum

When compared to the control subjects, the levels of IL-6 in CSF were increased both in patients with single GTCS and in patients with recurrent GTCS (p<0.001) (Fig. 1). Abnormal CSF levels (±2 SD of control levels) were detected in 11/16 patients with single GTCS and in 6/7 patients with recurrent GTCS. Furthermore, the CSF levels of IL-6 were significantly higher in patients with recurrent GTCS when compared to those with single GTCS (p=0.05). The serum levels of IL-6 were increased in all

Discussion

In patients with recent GTCS, we have previously found a rather selective increase in the levels of IL-6 and interleukin-1 receptor antagonist (IL-1ra) with unchanged interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels Peltola et al., 1998, Peltola et al., 2000a. The present study confirms and further extends these findings. The levels of IL-6 both in CSF and in serum were increased in all seizure groups (except in two CSF samples in PPS group). Furthermore, the magnitude of the

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