Impaired liver regeneration in mice by lipopolysaccharide via TNF-α/kallikrein-mediated activation of latent TGF-β

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.