Review: Regulation of liver regeneration by pro‐inflammatory cytokines

Abstract

The liver has tremendous regenerative capacity. This distinguishes it from other vital organs (e.g. the brain, heart and lungs) that cannot replace functional tissue once it has been destroyed. Although hepatocytes rarely proliferate in the healthy adult liver, virtually all surviving hepatocytes replicate at least once after 70% partial hepatectomy. Therefore, partial liver resection has been used to characterize mechanisms that regulate liver regeneration. Residual hepatocytes up-regulate both proliferative and liver-specific gene expression in order to preserve tissue specific function. In addition, hepatocyte proliferation is tightly co-ordinated to complement regenerative responses in hepatic non-parenchymal cells (e.g. endothelia, biliary epithelia, stellate and Kupffer cells), so that the entire organ can be reconstituted within days. Studies with neutralizing antibodies to tumour necrosis factor-alpha (TNF) clearly demonstrate that, after partial hepatectomy, TNF promotes liver cell proliferation. The present review focuses on the regulation of the hepatocyte proliferative response by pro-inflammatory cytokines.

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

“…This finding is consistent with other reports of an inability to detect changes in TNF protein levels after PH despite observing induction of mRNA for this cytokine (40,58). One possible explanation is that TNF is acting in a paracrine manner as has been previously suggested by Diehl and coworkers (59,60). Because we did not see a block or delay in DNA replication associated with the lack of Tnf induction in Myd88 KO mice, our results suggest that TNF may not be necessary for regeneration.…”

“…Other laboratories, including ours, have previously reported that TNF protein levels transiently increase after PH (6,64,65). Moreover, TNF promotes liver growth in vivo and hepatocyte proliferation in vitro (18, 59, 66 -68) and injection of TNF-neutralizing Abs blocks liver regeneration as well as multiple signaling pathways involved in this process (59,60). We also previously demonstrated that Tnfr1 KO have defective liver regeneration after PH and carbon tetrachloride induced injury (6,69).…”

“…Thus, a brief review of the evidence that leads to the hypothesis that TNF plays an important role in liver regeneration is warranted. More in-depth reviews on TNF and liver regeneration have been published (1,59,(61)(62)(63). Other laboratories, including ours, have previously reported that TNF protein levels transiently increase after PH (6,64,65).…”

Targeting of aminopeptidase n to bile canaliculi correlates with secretory activities of the developing canalicular domain

“…Recently, a number of sophisticated methods have been devised to culture hepatocytes for a longer period without losing their replicative potential and differentiation capacity; several key substances including various cytokines are required. 21,22,53,54 There is also evidence suggesting the importance of interactions between parenchymal and nonparenchymal liver cells (especially between hepatocytes and stellate cells) during liver regeneration. These studies have created new dimensions for hepatic investigation.…”

“…The molecular mechanism for the triggering is currently unknown, but several recent reports may have provided some intriguing hints. 21,22,54 …”