Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice

Abstract

The response to partial hepatectomy (PH) is impaired in interleukin 6 (IL-6)-deficient mice. IL-6 is well known for its role in the induction of the acute phase (AP) response, and the impairment of this response after surgery and hepatectomy could explain the defective hepatocyte regeneration. In addition, it was proposed that IL-6 has an important role in stimulating the reentry of quiescent cells into the cell cycle within the first 2 to 4 hours after PH. To further analyze the role for IL-6, we performed two third hepatectomies in wild-type mice, in IL-6 knockout (KO) mice, and in IL-6 KO mice that were treated 30 minutes before surgery with intravenous (IV) (short acting) or subcutaneous (SC) (long acting) injections of recombinant IL-6. The high postoperative mortality of IL-6 -deficient mice could be completely prevented by SC, but not by IV IL-6 treatment, showing the requirement of a sustained action of IL-6. However, there is a subset of IL-6 KO mice that survives a PH in good health even without IL-6 treatment. When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry. We conclude that the major role of IL-6 is the induction of an adaptive response to PH that ensures body homeostasis and survival. (HEPATOLOGY 2003;38:674-682.)

A20 Protects Mice From Lethal Radical Hepatectomy by Promoting Hepatocyte Proliferation via a p21waf1-Dependent Mechanism *

“…22 Mice with targeted disruption of IL-6 suffer liver failure and defective regeneration. 30,31 Liver regeneration is enhanced by a designer IL-6/soluble IL-6 receptor fusion protein with superagonistic IL-6 properties or upon overexpression of STAT3. 32,33 In addition, IL-6 prevents mortality following fatty liver transplants in rats.…”

A Critical Role for Matrix Metalloproteinases in Liver Regeneration

“…IL-6 initiates the acute phase response in the liver, and activates STAT3, a transcription factor that initiates hepatocyte replication (7). Therefore, it appears that IL-6 plays both a priming and mitogenic role in hepatic regeneration.…”

Metalloproteinase inhibitor TIMP‐1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration†

“…9 Mice deficient in TNF receptor 1 and interleukin 6 have increased mortality following PH. [10][11][12] TNF-␣ release from the cell surface is mediated by the metalloproteinase called TNF-␣-converting enzyme. 13,14 Tissue inhibitor of metalloproteinase 3 (TIMP-3) is the only known inhibitor of TNF-␣-converting enzyme.…”