Activation of c‐Jun‐N‐terminal kinase is critical in mediating lipopolysaccharide‐induced changes in the rat hippocampus

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Abstract
Lipopolysaccharide (LPS) exerts a myriad of effects in rat hippocampus; it increases the concentration of the proinflammatory cytokine, interleukin‐1β (IL‐1β), and signalling via the IL‐1 type I receptor (IL‐1RI) resulting in phosphorylation of the stress‐activated protein kinase, c‐jun‐N‐terminal kinase (JNK) and impairment in long‐term potentiation (LTP). This study was designed to establish whether activation of JNK is a pivotal event in mediating the effects of LPS in hippocampus and therefore LPS‐treated rats were injected intracerebroventricularly with saline, the JNK inhibitor D‐JNKI1, or with the anti‐inflammatory cytokine IL‐4, which antagonizes the effects of IL‐1β upstream of JNK activation. We report that IL‐4 blocked the LPS‐induced increase in IL‐1RI expression and associated increases in phosphorylation of JNK and c‐jun, whereas D‐JNKI1 inhibited the LPS‐induced phosphorylation of c‐jun. Both IL‐4 and D‐JNKI1 inhibited the increase in caspase‐3 staining which was associated with LPS treatment, and both abrogated the LPS‐induced inhibition of LTP in perforant path‐granule cell synapses. The data presented are consistent with the proposal that JNK activation, probably as a result of increased IL‐1RI activation, is a critical step in mediating the detrimental effects of LPS in hippocampus.