IL-18 deficiency aggravates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice due to an overcompensation by IL-12.
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.
Zhang
Xing-Mei
XM
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital in Huddinge, Stockholm, Sweden.
Duan
Rui-Sheng
RS
Chen
Zhiguo
Z
Quezada
Hernan Concha
HC
Mix
Eilhard
E
Winblad
Bengt
B
Zhu
Jie
J
D000222:Adaptation, Physiological; D000818:Animals; D001253:Astrocytes; D005260:Female; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000172:deficiency* / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia; D009043:Motor Activity; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000503:physiopathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index
D020382:Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D007608:Kainic Acid