Year: 2010
Type: dissertation
Abstract: The liver has the unique capability to regenerate its mass after damage and injury. Nevertheless liver failure is still a serious medical problem and enhancing the regenerative potential of the liver could be an effective and promising therapy. Interleukin-6 is known to play an important role in mediating pro-mitotic and pro-survival activities within the regenerative process. It already has been shown that IL-6 Transsignaling plays a crucial role in liver regeneration using the example of the effect of Hyper-IL-6 in accelerating liver regeneration following partial hepatectomy. Carbontetrachloride (CCl4) can be used to mimic drug induced hepatoxicity. Through the metabolization by cytochrome P450 dependent monooxygenase, the reactive CCl3• and CCL3O2• radicals are formed which can covalently bind to proteins, lipids and nucleic acids and this could lead to lipidperoxidation and liver damage. The aim of the present study was to investigate the impact of IL-6 Transsignaling on liver damage and regeneration in this CCl4 induced liver damage mouse model. Therefore mice were treated with substances either blocking IL-6 Transsignaling (soluble gp130Fc) or accelerating IL-6 Transsignaling (Hyper-IL-6). Afterwards the mice were treated intraperitoneally with a single dose of CCl4, leading to acute liver damage. Mice in which IL-6 Transsignaling was blocked displayed higher liver damage, becoming evident in enhanced lipid peroxidation 4 to 6 hours after CCl4 treatment. Subsequently ALT and AST serum levels were strongly increased from 24 to 48 hours after CCl4 treatment, with significantly higher levels in sgp130Fc pretreated mice. Moreover, uric acid and potassium serum level were elevated in mice with blocked IL-6 Transsignaling 48 hours after CCl4 injection. IL-6 serum level were elevated at early time points in mice pretreated with sgp130Fc compared to CCl4 only treated mice. As a consequence, acute phase genes like SAA1, SAA3 and haptoglobin were upregulated 6 hours after CCl4, although STAT-3 phosphorylation was diminished. When IL-6 Transsignaling was blocked by sgp130Fc, mRNA levels of SAA1 and SAA3 increased 6 fold, mRNA levels of haptoglobin increased 2 fold compared to CCl4 only treated animals. In addition, glycogen storage was altered after blockage of IL-6 Transsignaling. 24 hours after the damage all glycogen within the liver was consumed. While glycogen storages were filled up in livers of mice with normal or accelerated IL-6 Transsignaling, this process was significantly impaired when IL-6 Transsignaling was blocked. Animals pretreated with sgp130Fc showed lower BrdU incorporation, indicating a lower proliferation index. Overall, these data indicate a critical role of IL-6 Transsignaling in a CCl4 induced liver damage mouse model.
Author: Jessica Gewiese
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2564675953