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

• Published in: Experimental neurology 2007-05, Vol.205 (1), p.64-73
• Main Authors: Zhang, Xing-Mei, Duan, Rui-Sheng, Chen, Zhiguo, Quezada, Hernan Concha, Mix, Eilhard, Winblad, Bengt, Zhu, Jie
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; Astrocytes; Biological and medical sciences; Drug toxicity and drugs side effects treatment; Female; Gliosis - pathology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; IL-12; IL-18; Interferon-gamma - metabolism; Interleukin-12 - metabolism; Interleukin-18 - deficiency; Interleukin-18 - pharmacology; Kainic acid; Kainic Acid - pharmacology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Motor Activity; Nerve Degeneration - chemically induced; Nerve Degeneration - physiopathology; Nervous system (semeiology, syndromes); Neurodegeneration; Neurology; Pharmacology. Drug treatments; Recombinant Proteins - pharmacology; Severity of Illness Index; Toxicity: nervous system and muscle
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2007.01.019

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-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in the hippocampus by immunohistochemistry and flow cytometry. IL-12 and IFN-γ 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.