Impaired liver regeneration in mice by lipopolysaccharide via TNF-alpha/kallikrein-mediated activation of latent TGF-beta.
OBJECTIVE
Because impaired regeneration after surgical treatment of the liver is influenced by circulating endotoxin, the underlying molecular mechanism was investigated.


METHODS
Lipopolysaccharide (LPS) was injected intraperitoneally into mice, followed 24 hours later by 67% partial hepatectomy. We measured serum tumor necrosis factor (TNF) alpha levels as well as proliferating cell nuclear antigen labeling index, transforming growth factor (TGF) beta expression, and plasma kallikrein (PLK) activities in regenerating livers. We also examined the effect of LPS, TNF-alpha, and PLK on latent TGF-beta activation in homotypic and heterotypic cultures of rat or mouse hepatic stellate cells and Kupffer cells.


RESULTS
Serum TNF-alpha levels increased after LPS (500 ng/g body wt) injection and after partial hepatectomy, accompanying TGF-beta-mediated suppression of hepatic proliferating cell nuclear antigen labeling index. This suppression was mimicked by a combination of preadministration of 50 ng/g body wt LPS and postoperative administration of 5 ng/g body wt TNF-alpha. In vitro, LPS stimulated Kupffer cells to secrete TNF-alpha, which enhanced PLK activity on the hepatic stellate cell surface through increasing PLK binding, thereby inducing proteolytic activation of latent TGF-beta and its autoinduction. Blockade of TGF-beta, TNF-alpha, or PLK activity prevented LPS-induced impaired regeneration in vivo.


CONCLUSIONS
LPS provokes TNF-alpha/PLK-mediated proteolytic activation of latent TGF-beta in hepatic stellate cells, leading to impaired liver regeneration after partial hepatectomy.
Akita
Kuniharu
K
First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Okuno
Masataka
M
Enya
Masamichi
M
Imai
Shoko
S
Moriwaki
Hisataka
H
Kawada
Norifumi
N
Suzuki
Yasuhiro
Y
Kojima
Soichi
S
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D006498:Hepatectomy / Q000379:methods; D007610:Kallikreins / Q000097:blood / Q000502:physiology*; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007610:Kallikreins