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The Journal of Neuroscience, July 15, 2002, 22(14):5910-5919
Interleukin-18 Involvement in Hypoxic-Ischemic Brain Injury
Maj
Hedtjärn1,
Anna-Lena
Leverin1,
Kristina
Eriksson2,
Klas
Blomgren1, 3,
Carina
Mallard1, and
Henrik
Hagberg1, 4
Departments of 1 Physiology and Pharmacology,
2 Medical Microbiology and Immunology,
3 Pediatrics, and 4 Obstetrics and Gynecology,
Perinatal Center, Göteborg University, 405 30 Göteborg,
Sweden
Inflammation is a critical factor for development of
hypoxic-ischemic (HI) brain injury. Interleukin-18 (IL-18) is a
proinflammatory cytokine expressed in microglia and processed by
caspase-1. Our aim was to characterize the expression of IL-18 and its
receptor in relation to caspase-1 and IL-1 after HI and to evaluate
to what extent IL-18 contributes to HI brain injury. Seven-day-old rats
were subjected to HI, and brain tissue was sampled at different time
points (3 hr to 14 d) after insult. The mRNA for IL-18 and caspase-1 were analyzed with reverse transcriptase PCR, protein was
analyzed by Western blot (IL-18, caspase-1) or ELISA (IL-1), and the
regional distribution was assessed by immunohistochemistry. HI was also
induced in C57BL/6 mice, and brain injury in IL-18-deficient animals
was compared with that in wild-type animals. The expression of
mRNA/protein for caspase-1 and IL-18 in brain homogenates increased progressively at 12 hr to 14 d after HI, whereas IL-1 peaked at
8 hr. A widespread expression of caspase-1 and IL-18 protein in
microglia was found in the HI hemisphere. The IL-18 receptor was
expressed on neurons of the cerebral cortex and thalamus. IL-1 was
primarily found in microglia in the habenular nucleus of the thalamus.
The infarct volume was reduced by 21% (p = 0.01), and the neuropathology score was significantly decreased in the cerebral cortex ( 35%), hippocampus (22%), striatum (18%), and thalamus (17%) in mice with IL-18 deficiency compared with wild-type mice. In conclusion, we found that IL-18 expression in microglia was
markedly increased after HI and that IL-18 appears to be important for
the development of HI brain injury.
Key words:
IL-18; caspase-1; IL-1; neonatal; inflammation; microglia
Copyright © 2002 Society for Neuroscience 0270-6474/02/22145910-10$05.00/0
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