Potent effect of interleukin-1β to evoke ATP and adenosine release from rat hippocampal slices

https://doi.org/10.1016/j.jneuroim.2004.02.004Get rights and content

Abstract

In this study the effect of IL-1β on [3H]purine release from rat hippocampal slices was explored. IL-1β (3×10−18–3×10−14 M) concentration-dependently elevated the basal [3H]purine efflux, and this effect was reversed by the selective IL-1RI receptor antagonist IL-1ra (10−12 M). HPLC analysis revealed that the amount of [3H]ATP and [3H]adenosine significantly increased in the effluent in response to IL-1β. The sodium channel inhibitor tetrodotoxin, the NMDA and non-NMDA receptor antagonists d(−)-2-amino-5-phosphonopentanoic acid (AP-5) plus 6-cyano-7-nitroquinoxaline-2,3-dione-disodium (CNQX) almost completely abolished IL-1β-evoked [3H]purine release. The effect of IL-1β on [3H]purine efflux was also prevented by the p38 MAP kinase inhibitor SB 203580, by the nucleoside transport inhibitor nitrobenzyl-thioinosine (NBTI) and by low temperature (4 °C). In summary IL-1β triggers  a transporter mediated [3H]purine efflux in the hippocampus which is conveyed by glutamate receptor activation and the p38 MAP kinase pathway, and could serve as a mediator of IL-1β-induced synaptic depression.

Introduction

IL-1β is well known as a cellular mediator of inflammation, acute and chronic neuronal degeneration, and the following repair process in the brain Allan and Rothwell, 2001, Rothwell and Luheshi, 2000, Szelenyi, 2001. Thus, the diverse actions of IL-1β  upon inflammatory stimuli are extensively characterized, including neurotoxic action, fever and sickness behavior. Although the basal expression level and the exact source of IL-1β in the normal brain is controversial (Vitkovic et al., 2000), receptors sensitive to low level of IL-1β are constitutively expressed in the rodent hippocampus Ban et al., 1991, Cunningham et al., 1991, Ericsson et al., 1995, Parnet et al., 1994, Takao et al., 1990. Furthermore IL-1β exert remarkable electrophysiological actions in this brain area: in higher concentration it inhibits (O'Connor and Coogan, 1999), whilst in lower concentrations it contributes to the maintenance of long-term potentiation Schneider et al., 1998, Ross et al., 2003, and inhibits excitatory synaptic transmission in the CA1 region (Luk et al., 1999) with a presynaptic site of action. This latter effect, however, seems to be indirect, being sensitive to A1-adenosine receptor blockade. Adenosine is well known as an endogenous neuroprotectant (Ribeiro et al., 2003) and anti-inflammatory mediator (Cronstein, 1994) and this finding implies that there is a functional link between IL-1β and adenosinergic signalling in the hippocampus, and that IL-1β might release adenosine or a related purine. Adenosine A1 receptors are strongly expressed in the hippocampus at presynaptic nerve terminals Deckert and Jorgensen, 1988, Fastbom et al., 1987, Rebola et al., 2003; their activation decreases glutamate release from excitatory nerve terminals Burke and Nadler, 1988, Corradetti et al., 1984, Sehmisch et al., 2001, and previous studies demonstrated the stimulation dependent release of ATP and adenosine and their extracellular interconversion in this brain area Cunha et al., 1996, Cunha et al., 1998. Nevertheless, the exact link between the effect of IL-1β and adenosine receptor activation have not been explored. Therefore our aim was to determine how IL-1β affect the extracellular level of purines in superfused hippocampal slices, preloaded with [3H]adenosine.

Section snippets

Materials and methods

All studies were conducted in accordance with the principles and procedures outlined in the NIH Guide for the Care and use of Laboratory animals and were approved by the local Animal Care Committee of the Institute of Experimental Medicine (Budapest, Hungary).

Results

The radioactivity uptake of the hippocampal slices was 1.124±0.14×106 Bq/g (n=12) and the basal [3H]purine efflux was 0.35±0.02% (n=12). Electrical field stimulation elicited a TTX-sensitive and reproducible elevation of tritium efflux (EFS1=1.34±0.23%, n=6) resulting in an EFS2/EFS1 ratio closed to one (1.09±0.22%, n=6). Ten-minute superfusion of the slices with IL-1β (5×10−15 M)  significantly elevated the basal [3H]purine level in the effluent, and this effect was concentration-dependent

Discussion

Our data demonstrate that low concentration of IL-1β releases [3H]purines from rat hippocampal slices and this release involves (1) glutamate receptor mediated excitatory synaptic transmission, (2) IL-1RI receptor and subsequent p38 MAP kinase activation, (3) reversal of the equilibrative nucleoside carrier.

The effect of IL-1β on [3H]purine release was concentration-dependent, reversible, and was observed with similar time frame to its depressant effect on hippocampal EPSC recordings (Luk et

Acknowledgements

This study was supported by the grants of the Hungarian Research Foundation (OTKA T037457, TS040736), Hungarian Medical Research Council, National Institutes of Health grant GM66189 (G. Hasko), the Centre of Excellence Grant of EU Framework Program 5 (ICA1-CT-2000-70004) and by the Volkswagen Foundation. The authors are grateful to Ms. Zsuzsanna Körössy for excellent technical assistance.

References (50)

  • C.A. Murray et al.

    Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged rats

    Neurobiol. Aging

    (1997)
  • L.A. O'Neill et al.

    The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense

    Immunol. Today

    (2000)
  • P. Parnet et al.

    Expression of type I and type II interleukin-1 receptors in mouse brain

    Mol. Brain Res.

    (1994)
  • N. Rebola et al.

    Subcellular localization of adenosine A1 receptors in nerve terminals and synapses of the rat hippocampus

    Brain Res.

    (2003)
  • F.M. Ross et al.

    A dual role for interleukin-1 in LTP in mouse hippocampal slices

    J. Neuroimmunol.

    (2003)
  • N.J. Rothwell et al.

    Interleukin 1 in the brain: biology, pathology and therapeutic target

    Trends Neurosci.

    (2000)
  • B. Sperlágh et al.

    Neuronal synthesis, storage and release of ATP

    Semin. Neurosci.

    (1996)
  • B. Sperlágh et al.

    Ischemic-like condition releases norepinephrine and purines from different sources in superfused rat spleen strips

    J. Neuroimmunol.

    (2000)
  • T. Suzuki et al.

    Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia

    J. Neurosci.

    (2004)
  • J. Szelenyi

    Cytokines and the central nervous system

    Brain Res. Bull.

    (2001)
  • E.S. Vizi

    Different temperature dependence of carrier-mediated (cytoplasmic) and stimulus-evoked (exocytotic) release of transmitter: a simple method to separate the two types of release

    Neurochem. Int.

    (1998)
  • S.M. Allan et al.

    Cytokines and acute neurodegeneration

    Nat. Rev. Neurosci.

    (2001)
  • S.P. Burke et al.

    Regulation of glutamate and aspartate release from slices of the hippocampal CA1 area: effects of adenosine and baclofen

    J. Neurochem.

    (1988)
  • H.V. Carswell et al.

    Kainate-evoked release of adenosine from the hippocampus of the anaesthetised rat: possible involvement of free radicals

    J. Neurochem.

    (1997)
  • Y. Chen et al.

    Release of endogenous adenosine and its metabolites by the activation of NMDA receptors in the rat hippocampus in vivo

    Br. J. Pharmacol.

    (1992)
  • Cited by (0)

    View full text