Abstract
BackgroundTissue inhibitor of metalloproteinase 1 (TIMP-1), which is thought to be produced mainly by activated hepatic stellate cells and Kupffer cells in the liver, plays a pivotal role in matrix remodeling during liver injury and repair; while the effect of TIMP-1 on hepatocellular damage remains obscure.ResultsHepatic expression of TIMP-1 mRNA and protein was up-regulated both in acute and chronic liver injury induced by carbon tetrachloride (CCl4). Compared with wild-type mice, TIMP-1 knockout mice were more susceptible to CCl4-induced acute and chronic liver injury, as shown by higher levels of serum alanine aminotransferase (ALT), greater number of apoptotic hepatocytes, and more extended necroinflammatory foci. TIMP-1 knockout mice also displayed greater degree of liver fibrosis after chronic CCl4 injection when compared with wild-type mice. In vitro treatment with TIMP-1 inhibited cycloheximide-induced cell death of primary mouse hepatocytes. Finally, up-regulation of TIMP-1 in the liver and serum after chronic CCl4 treatment was markedly diminished in hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. In vitro treatment with interleukin-6 stimulated TIMP-1 production in primary mouse hepatocytes, but to a lesser extent in STAT3-deficient hepatocytes.ConclusionsTIMP-1 plays an important role in protecting against acute and chronic liver injury and subsequently inhibiting liver fibrosis induced by CCl4. In addition to activated stellate cells and Kupffer cells, hepatocytes are also responsible for TIMP-1 production during liver injury via a STAT3-dependent manner.
Highlights
Chronic liver fibrosis induced by viral hepatitis, alcohol abuse, and nonalcoholic steatohepatitis is a major cause of morbidity and mortality worldwide [1]
Early studies showed Tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA and protein expression are up-regulated by inflammatory cytokines in rat hepatocytes [22,23], the precise roles of tissue inhibitors of metalloproteinases (TIMPs)-1 produced by hepatocytes in liver injury remain largely unknown
We found that TIMP-1-deficient (TIMP-1-/-) mice were more susceptible to CCl4induced liver injury and fibrosis, suggesting the protective feature of TIMP-1 in liver injury
Summary
Up-regulation of TIMP-1 in acute and chronic liver injury after CCl4 exposure To determine the expression of TIMP-1 during the course of acute and chronic liver injury, real-time PCR and ELISA analyses were performed on liver samples. Deletion of STAT3 in hepatocytes reduces hepatic and serum levels of TIMP-1 after chronic CCl4 treatment To further confirm the critical role of hepatocyte STAT3 in the induction of TIMP-1 during chronic liver injury in vivo, we compared the production of TIMP-1 between wild-type and STAT3Hep-/- mice 6 and 24 h after a 4-week chronic CCl4 treatment. That TIMP-1 was stained strongly in hepatocytes from the livers of mice with acute and chronic CCl4 treatment These findings suggest that in addition to HSCs and Kupffer cells, hepatocytes are a source for TIMP-1 production which is controlled partially by STAT3 during chronic liver injury. TIMP-1 plays dual roles in regulating liver fibrosis by inhibiting liver fibrosis via protecting against liver injury or by promoting liver fibrosis via protecting against HSC death
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
