Activation of p38 Plays a Pivotal Role in the Inhibitory Effect of Lipopolysaccharide and Interleukin-1β on Long Term Potentiation in Rat Dentate Gyrus

Áine Kelly,Emily Vereker,Yvonne Nolan,Marcella Brady,Claire Barry,Christine E Loscher,Kingston H.G Mills,Marina A Lynch

doi:10.1074/jbc.m301938200

Abstract

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally. It has recently been reported that intraperitoneal injection of LPS inhibited long term potentiation (LTP) in perforant path-granule cell synapses and that this effect was coupled with an increase in the concentration of the proinflammatory cytokine, interleukin-1 beta (IL-1 beta). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1 beta may mediate the effects of LPS. Here we report that the inhibition of LTP induced by LPS and IL-1 beta was coupled with stimulation of the stress-activated protein kinase p38 in hippocampus and entorhinal cortex and that this effect was abrogated by the p38 inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL-1RI-/- mice. The data also indicate that activation of the transcription factor, nuclear factor kappa B (NF kappa B), may play a role, since the inhibitory effect of LPS and IL-1 beta on LTP was attenuated by the NF kappa B inhibitor, SN50; consistently, LPS and IL-1 beta led to activation of NF kappa B in entorhinal cortex. We suggest that one consequence of these LPS and IL-1 beta-induced changes is a compromise in glutamate release in dentate gyrus, which was coupled with the inhibition of LTP. The evidence is consistent with the idea that the LPS-induced impairment in LTP is mediated by IL-1 beta and is a consequence of activation of p38.

Highlights

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally
We report that the inhibition of long term potentiation (LTP) induced by LPS and IL-1␤ was coupled with stimulation of the stress-activated protein kinase p38 in hippocampus and entorhinal cortex and that this effect was abrogated by the p38 inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL-1RI؊/؊ mice
We conclude that the glutamate-Naϩ exchanger does not contribute significantly to the concentration of glutamate in our samples. These findings suggest that IL-1␤-induced activation of p38 and nuclear factor ␬B (NF␬B) exerted a negative effect on glutamate release, and since the cell bodies of the synapses at which this effect occurs are located in the entorhinal cortex, we argued that evidence of activation of p38 and NF␬B may extend to this area

Summary

Introduction

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally. Activation of JNK and p38 is coupled with elevated IL-1␤ concentrations in aged rats [13] and in rats treated intracerebroventricularly with IL-1␤ [6], and the LTP-associated increase in KCl-stimulated glutamate release is attenuated in both experimental conditions [6, 13]. This is consistent with the observation that IL-1␤ inhibits transmitter release, for example release of acetylcholine [14] and glutamate [15] in hippocampal synaptosomes. Powerful evidence from in vitro studies, and in vivo studies using knock-out mice, supports an anti-apoptotic role for NF␬B [33,34,35,36,37,38]

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