Activation of c-Jun-N-terminal kinase is critical in mediating lipopolysaccharide-induced changes in the rat hippocampus.
Lipopolysaccharide (LPS) exerts a myriad of effects in rat hippocampus; it increases the concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta), 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-1beta 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.
Barry
Claire E
CE
Trinity College Institute of Neuroscience, Department of Physiology, Trinity College, Dublin, Ireland.
Nolan
Yvonne
Y
Clarke
Rachael M
RM
Lynch
Aileen
A
Lynch
Marina A
MA
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry / Q000379:methods; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016755:Proto-Oncogene Proteins c-jun; D017472:Receptors, Interleukin-1; D015847:Interleukin-4; D048031:JNK Mitogen-Activated Protein Kinases