Enhanced liver regeneration in IL10 deficient mice after partial hepatectomy via activating hepatocyte STAT3 and stimulating inflammatory response (134.6)

Abstract

Abstract A series of evidence show that pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), play a critical role in the initiation and progress of liver regeneration. Relatively little is known regarding the role of anti-inflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. IL-10 -/- mice, and IL10-/-STAT3hep-/- double knockout mice in which IL-10 gene was globally disrupted and STAT3 gene was deleted specifically in hepatocytes; and their littermate controls underwent 70% PHx. Liver regeneration was evaluated by BrdU incorporation. After PHx, expression of IL-10 mRNA was significantly elevated after PHx. Compared to wild type mice, IL-10-/- mice had enhanced liver regeneration as determined by measuring hepatocyte proliferation and mitosis with the peak of hepatocyte proliferation occurring 48 hours post PHx. This increased liver regeneration in IL-10-/- mice was associated with elevated serum levels of TNF-alpha and IL-6, and enhanced activation of the IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes reduced liver regeneration in IL-10-/- mice. These findings suggest that IL-10 may negatively regulate liver regeneration via limiting inflammatory cytokine responses and subsequently tempering hepatic STAT3 activation.