TY - JOUR
T1 - Impaired liver regeneration in mice by lipopolysaccharide via TNF-α/kallikrein-mediated activation of latent TGF-β
AU - Akita, Kuniharu
AU - Okuno, Masataka
AU - Enya, Masamichi
AU - Imai, Shoko
AU - Moriwaki, Hisataka
AU - Kawada, Norifumi
AU - Suzuki, Yasuhiro
AU - Kojima, Soichi
PY - 2002
Y1 - 2002
N2 - Background & Aims: 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) α levels as well as proliferating cell nuclear antigen labeling index, transforming growth factor (TGF) β expression, and plasma kallikrein (PLK) activities in regenerating livers. We also examined the effect of LPS, TNF-α, and PLK on latent TGF-β activation in homotypic and heterotypic cultures of rat or mouse hepatic stellate cells and Kupffer cells. Results: Serum TNF-α levels increased after LPS (500 ng/g body wt) injection and after partial hepatectomy, accompanying TGF-β-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-α. In vitro, LPS stimulated Kupffer cells to secrete TNF-α, which enhanced PLK activity on the hepatic stellate cell surface through increasing PLK binding, thereby inducing proteolytic activation of latent TGF-β and its autoinduction. Blockade of TGF-β, TNF-α, or PLK activity prevented LPS-induced impaired regeneration in vivo. Conclusions: LPS provokes TNF-α/PLK-mediated proteolytic activation of latent TGF-β in hepatic stellate cells, leading to impaired liver regeneration after partial hepatectomy.
AB - Background & Aims: 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) α levels as well as proliferating cell nuclear antigen labeling index, transforming growth factor (TGF) β expression, and plasma kallikrein (PLK) activities in regenerating livers. We also examined the effect of LPS, TNF-α, and PLK on latent TGF-β activation in homotypic and heterotypic cultures of rat or mouse hepatic stellate cells and Kupffer cells. Results: Serum TNF-α levels increased after LPS (500 ng/g body wt) injection and after partial hepatectomy, accompanying TGF-β-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-α. In vitro, LPS stimulated Kupffer cells to secrete TNF-α, which enhanced PLK activity on the hepatic stellate cell surface through increasing PLK binding, thereby inducing proteolytic activation of latent TGF-β and its autoinduction. Blockade of TGF-β, TNF-α, or PLK activity prevented LPS-induced impaired regeneration in vivo. Conclusions: LPS provokes TNF-α/PLK-mediated proteolytic activation of latent TGF-β in hepatic stellate cells, leading to impaired liver regeneration after partial hepatectomy.
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U2 - 10.1053/gast.2002.34234
DO - 10.1053/gast.2002.34234
M3 - Article
C2 - 12105863
AN - SCOPUS:0036301212
VL - 123
SP - 352
EP - 364
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 1
ER -