Eosinophil-induced liver injury: an experimental model using IL-5 transgenic mice.
OBJECTIVE
In certain liver diseases, activated eosinophils are considered to be important effector cells in addition to T-cell-mediated cytotoxicity. No experimental model, however, has been developed for in vivo analysis of the cytotoxic mechanisms.


METHODS
Interleukin-5 (IL-5) transgenic mice (C3H/HeN-TgN(IL-5)Imeg), which exhibit marked eosinophilia without liver injury, were injected once with 25 microg of lipopolysaccharide (LPS) intraperitoneally. The mice were sacrificed weekly and eosinophilic injuries were assessed microscopically. To clarify the role of Kupffer cells and tumor necrosis factor-alpha (TNF-alpha) in the liver injury, gadolinium chloride (GdCl3) and anti-TNF-alpha neutralizing antibody were administrated before the LPS injection.


RESULTS
Two weeks after injection, transgenic mice exhibited marked infiltration of eosinophils and extensive lobular necrosis. Transmigration of eosinophils through vascular endothelium and degranulation of eosinophil cytotoxic granules in inflamed areas were observed. These eosinophilic injuries were transient, but liver-specific. Pre-administration of GdCl3 and anti-TNF-alpha markedly reduced the hepatic inflammation, suggesting that LPS-activated Kupffer cells play a key role in producing the cytotoxicity of eosinophils by releasing TNF-alpha.


CONCLUSIONS
We have established an experimental model of eosinophil-induced liver injury using IL-5 transgenic mice. Since this model is simple and highly reproducible, it will be useful for analysis of in vivo cytotoxic mechanisms of eosinophils.
The First Department of Internal Medicine, Kochi Medical School, Japan.
K
K
Tsuda
T
T
Maeda
A
A
Tominaga
Y
Y
Watanabe
E
E
Miyazaki
H
H
Enzan
N
N
Akisawa
S
S
Iwasaki
T
T
Saibara
S
S
Onishi
D000818:Animals; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D015848:Interleukin-5 / Q000235:genetics*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000276:immunology* / Q000293:injuries* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D015848:Interleukin-5; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005682:Gadolinium; C038958:gadolinium chloride