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

J Neurochem. 2005 Apr;93(1):221-31. doi: 10.1111/j.1471-4159.2004.03011.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Drug Interactions
  • Electric Stimulation / methods
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Hippocampus / cytology*
  • Immunohistochemistry / methods
  • Interleukin-4 / metabolism
  • Interleukin-4 / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / radiation effects
  • Male
  • Models, Biological
  • Neurons / drug effects*
  • Neurons / metabolism
  • Patch-Clamp Techniques / methods
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Interleukin-1 / metabolism


  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-jun
  • Receptors, Interleukin-1
  • Interleukin-4
  • JNK Mitogen-Activated Protein Kinases