Lipopolysaccharide, a component of the cell wall of Gram-negative bacteria, may be responsible for at least some of the pathophysiological sequelae of bacterial infections, probably by inducing an increase in interleukin-1␤ (IL-1␤) concentration. We report that intraperitoneal injection of lipopolysaccharide increased hippocampal caspase-1 activity and IL-1␤ concentration; these changes were associated with increased activity of the stress-activated kinase c-Jun NH 2 -terminal kinase, decreased glutamate release, and impaired long term potentiation. The degenerative changes in hippocampus and entorhinal cortical neurones were consistent with apoptosis because translocation of cytochrome c and poly(ADP-ribose) polymerase cleavage were increased. Inhibition of caspase-1 blocked these changes, suggesting that IL-1␤ mediated the lipopolysaccharide-induced changes.There is increasing awareness of the existence of bidirectional communication between the immune and nervous systems. The proinflammatory cytokine, interleukin-1␤ (IL-1␤), 1 is one molecule that may play a pivotal role in integrating neuronal immune responses with those of the endocrine system because it exerts significant effects in all systems, for example in response to stressors such as infection. Gram-negative bacterial infections are associated with multiple pathophysiological changes; it is widely accepted that these changes are stimulated by lipopolysaccharide (LPS), a component of the outer membrane of most Gram-negative bacteria. These changes, which include fever, changes in sleep pattern, and anorexia (1), are mimicked by, and therefore thought to be mediated through production of, IL-1␤. Thus LPS, injected centrally or peripherally, increases IL-1␤ concentrations (2, 3) and IL-1␤ mRNA expression (4) in rat brain.Although it appears that in certain circumstances IL-1␤ may be neuroprotective, the consensus is that prolonged exposure, or exposure of tissue to high concentrations of IL-1␤, results in degenerative changes (5). Therefore it is significant that increased IL-1 concentrations in different brain areas have been correlated with neurodegenerative disorders such as Down syndrome, Alzheimer's disease (6), and Parkinson's disease (7), whereas in experimental models, IL-1␤ is considered to be responsible for the cell damage associated with ischemia (8) and excitotoxicity (9) and is increased after experimental traumatic lesions (10). A striking example of a neuronal deficit induced by IL-1␤ is the impairment in long term potentiation (LTP) in the hippocampus in vitro (11-13) and in vivo (14 -16).IL-1␤ is produced by glia (17, 18) and neurones (19,20) in response to tissue stress. It is cleaved from the inactive percursor, pro-IL-1␤, by the action of caspase-1, a member of a large family of cysteine proteases that have been implicated in apoptotic cell death (21-25). It might be predicted therefore that any trigger such as LPS, which induces an increase in IL-1␤, will do so by increasing activity of caspase-1.Our objective was to investigate th...

Long-term potentiation (LTP) in perforant path-granule cell synapses is decreased in aged rats, stressed rats, and rats injected intracerebroventricularly with the proinflammatory cytokine interleukin-1␤ (IL-1␤). One factor that is common to these experimental conditions is an increase in the concentration of IL-1␤ in the dentate gyrus, suggesting a causal relationship between the compromise in LTP and increased IL-1␤ concentration. In this study, we have investigated the downstream consequences of an increase in IL-1␤ concentration and report that the reduced LTP in rats injected intracerebroventricularly with IL-1␤ was accompanied by a decrease in KCl-stimulated glutamate release in synaptosomes prepared from dentate gyrus, although unstimulated glutamate release was increased. These changes were paralleled by increased activity of the stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. Intracerebroventricular injection of IL-1␤ increased reactive oxygen species production in hippocampal tissue, whereas IL-1␤ and H 2 O 2 increased activities of both JNK and p38 in vitro. Dietary manipulation with antioxidant vitamins E and C blocked the increase in reactive oxygen species production, the stimulation of JNK and p38 activity, the attenuation of glutamate release, and the IL-1␤-induced inhibitory of LTP. We propose that IL-1␤ stimulates activity of stress-activated kinases, which in turn may inhibit glutamate release and result in compromised LTP and that these actions are a consequence of increased production of reactive oxygen species.Key words: LTP; dentate gyrus; IL-1␤; stress-activated kinases; glutamate release; reactive oxygen species Consistent with the high expression of IL-1 receptors in the hippocampus (Lechan et al., 1990;Ban et al., 1991;Parnet et al., 1994) are several observed effects of exogenous IL-1 in this brain area. For example, IL-1␤ exerts an inhibitory effect on (1) long-term potentiation (LTP) in CA1 (Bellinger et al., 1993), CA3 (Katsuki et al., 1990), and dentate gyrus (Cunningham et al., 1996; Murray and Lynch, 1998a,b), (2) release of acetylcholine (Rada et al., 1991) and glutamate (Murray et al., 1997) in hippocampal synaptosomes, (3) calcium influx in hippocampal synaptosomes (Murray et al., 1997), and (4) Ca 2ϩ channel currents in hippocampal neurons (PlataSalaman and ffrench-Mullen, 1994).The mechanism by which IL-1␤ inhibits LTP remains to be established. Because maintenance of LTP has been associated with increased glutamate release (Bliss and Collingridge, 1993;Canevari et al., 1994;McGahon and Lynch, 1996;McGahon et al., 1997), one factor that may contribute to inhibition of LTP is the inhibitory effect of IL-1␤ on glutamate release. However, it has been recently reported that the IL-1␤-induced attenuation of LTP in dentate gyrus in vitro is blocked by SB203580 (Coogan et al., 1997), an inhibitor of p38 that is one member of the family of mitogenactivated protein (MAP) kinases. The MAP kinase family has been identified as a major ...

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␤ (IL-1␤). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1␤ may mediate the effects of LPS. Here we report that the inhibition of 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. The data also indicate that activation of the transcription factor, nuclear factor B (NFB), may play a role, since the inhibitory effect of LPS and IL-1␤ on LTP was attenuated by the NFB inhibitor, SN50; consistently, LPS and IL-1␤ led to activation of NFB in entorhinal cortex. We suggest that one consequence of these LPSand IL-1␤-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␤ and is a consequence of activation of p38.The proinflammatory cytokine, interleukin-1␤ (IL-1␤), 1 exerts numerous effects in the central nervous system; among these effects is inhibition of long term potentiation (LTP) in the hippocampus (1-6). LTP in perforant path-granule cell synapses has been shown to be attenuated in aged and stressed rats (4, 5) and in rats that were treated intraperitoneally with lipopolysaccharide (LPS; Ref. 7) or intracerebroventricularly with IL-1␤ (4, 5); IL-1␤ concentration in hippocampus was increased in each of these experimental conditions, and a negative correlation between the ability of rats to sustain LTP and IL-1␤ concentration in hippocampus has been described previously (8, 9). The finding that the effect of LPS on LTP is mimicked by IL-1␤, together with the finding that the effect of LPS on LTP was abrogated by inhibiting IL-1␤ converting enzyme (caspase-1; Ref. 7), suggested that IL-1␤ may mediate this effect of LPS.Among the downstream effects of IL-1␤ is activation of the mitogen-activated protein kinases, c-Jun NH 2 -terminal kinase (JNK), or stress-activated protein kinase (SAPK) and p38; this effect has been reported in several tissues, for example, IL-1␤ increases activity of p38 in Chinese hamster CCl39 (10) and HeLa (11) cells, while IL-1␤-induced activation of JNK has been reported in human glomerular mesangial (12) and HeLa (11) cells. In the hippocampus, 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 rele...

Several effects of the proinflammatory cytokine, interleukin-1␤ (IL-1␤), have been described in the central nervous system, and one area of the brain where marked changes have been reported is the hippocampus. Among these changes are an IL-1␤-induced inhibition of long term potentiation (LTP) in perforant path-granule cell synapses and an attenuation of glutamate release in synaptosomes prepared from the hippocampus. Evidence suggests that, at least in circulating cells, the anti-inflammatory cytokine, IL-10, antagonizes certain effects of IL-1. We investigated the effect of IL-10 on IL-1␤-induced inhibition of LTP and glutamate release. The evidence presented indicates that IL-1␤ stimulates the stress-activated protein kinase, c-Jun-activated protein kinase (JNK), and IL-1 receptor-associated kinase, which may explain its inhibitory effect on release and LTP, and that IL-10 reversed the IL-1␤-induced stimulation of JNK activity and inhibition of release and LTP. We observed that IL-10 abrogated the stimulatory effect of IL-1␤ on superoxide dismutase activity and reactive oxygen species production, whereas the H 2 O 2 -induced inhibition of LTP was also blocked by IL-10. We present evidence that suggests that the action of IL-10 may be mediated by its ability to induce shedding of the IL-1 type I receptor.

The age-related impairment in long-term potentiation in the rat dentate gyrus is coupled with an increase in the proinflammatory cytokine, interleukin-1beta (IL-1beta). It is possible that this increase in IL-1beta might be a consequence of the age-related increase in reactive oxygen species production in hippocampal tissue. In this study we set out to identify the underlying cause of the age-related increase in reactive oxygen species production and to establish whether any consequences of such a change might impact on the ability of aged rats to sustain long-term potentiation (LTP). We report that there was an age-related increase in the activity of superoxide dismutase but no parallel increases in activities of glutathione peroxidase or catalase, while age-related decreases in the concentration of the scavengers, vitamins E and C and glutathione were also observed. We propose that these compromises in antioxidative strategies may result in an increase in reactive oxygen species production. The data described indicate that IL-1beta and H2O2 increase the activity of two stress-activated mitogen-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 in vitro, while age-related increases in both kinases were observed. We propose that the endogenous increase in these parameters which occurs with age induces the increase in activity of the stress-activated kinases, which in turn impacts on the ability of the aged rat to sustain LTP.

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The p75 neurotrophin receptor (p75NTR) potentiates Trk signaling, but the underlying mechanisms remain uncertain. Here, we examine the relationship between p75NTR cleavage and Trk signaling. We found that, in PC12 cells, nerve growth factor (NGF) induces rapid and robust α-secretase- and γ-secretase-dependent cleavage of p75NTR, releasing the resulting intracellular domain into the cytosol. Brain-derived neurotrophic factor similarly induces p75NTR cleavage in primary cerebellar granule neurons. p75NTR cleavage occurs by means of Trk-dependent activation of MEK-Erk signaling and induction of α-secretase activity, and is independent of ligand binding to p75NTR. Neurons and PC12 cells lacking p75NTR display defects in neurotrophin-dependent Akt activation. Normal Akt activation is rescued using full-length p75NTR or the p75 intracellular domain, but not cleavage-resistant p75NTR. We then demonstrate that NGF-dependent growth arrest of PC12 cells requires p75NTR cleavage and generation of the intracellular domain. We conclude that generation of the soluble p75NTR intracellular domain by Trk-induced cleavage plays a fundamental role in Trk-dependent signaling events.

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