IL-18 deficiency aggravates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice due to an overcompensation by IL-12

Exp Neurol. 2007 May;205(1):64-73. doi: 10.1016/j.expneurol.2007.01.019. Epub 2007 Jan 25.


The role of interleukin-18 (IL-18) in excitotoxic neurodegeneration is largely unknown. To address this issue, we used kainic acid (KA)-induced hippocampal neurodegeneration in IL-18 knockout (KO) mice. One day after KA administration, clinical symptoms and histopathological changes did not differ between IL-18 KO mice and wild-type mice. However, 7 days after KA application the hippocampal neurodegeneration was markedly severe in IL-18 KO mice as demonstrated by increased locomotion and prominent histopathological changes including neuronal cell loss, microglia activation and astrogliosis. Surprisingly, when wild-type mice received recombinant mouse IL-18 (rmIL-18) in advance, after KA treatment both the clinical and pathological signs were dose-dependently aggravated compared to mice without rmIL-18 pre-treatment. To clarify the mechanism behind this, we assessed the expression of the IL-18 associated cytokines IL-12, IL-1beta, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus by immunohistochemistry and flow cytometry. IL-12 and IFN-gamma expression was strongly increased in IL-18 KO mice when compared to wild-type mice 7 days after KA treatment in agreement with increased microglia activation. These results suggest that the role of IL-18 in excitotoxic injury in IL-18 deficient mice may be overcompensated by increased IL-12 secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Animals
  • Astrocytes
  • Female
  • Gliosis / pathology
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Hippocampus* / physiopathology
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism*
  • Interleukin-18 / deficiency*
  • Interleukin-18 / pharmacology
  • Kainic Acid* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia
  • Motor Activity
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / physiopathology*
  • Recombinant Proteins / pharmacology
  • Severity of Illness Index


  • Interleukin-18
  • Recombinant Proteins
  • Interleukin-12
  • Interferon-gamma
  • Kainic Acid