Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Abstract

Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of antiinflammatory 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. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10 ؊/؊ mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-␣, and IFN-␥) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10 ؊/؊ mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10 ؊/؊ mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10 ؊/؊ mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.

Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target

“…Expression of IL-10 in the liver is upregulated after PHx 69. Disruption of IL-10 enhances liver inflammation and regenerative responses with increased STAT3 activation in the liver 69.…”

Regenerative Wound Healing: The Role of Interleukin-10

“…IL-10 knockout mice demonstrate enhanced hepatocyte regeneration and proliferation compared with control mice. 48 …”

Impact of NKT Cells and LFA-1 on Liver Regeneration under Subseptic Conditions

“…As CCL5 is a known NK cell attractor [16], elevated levels of CCL5 in the liver of the LFA-1-deficient mice 24h after PH might account for increased numbers of NK cells. In addition, mRNA of the immunosuppressive cytokine IL10, known to be produced by NK cells during acute and systemic infections [17] and to negatively regulate hepatocyte proliferation [18], was found to be significantly increased in LFA-1 -/- compared to WT mice at 24h after PH and LPS application (Fig 5B). Besides its immunosuppressive effect, IL-10 affects the synthesis of IL-12 [19], and IL-12 is well known as a cytokine of indirect NKT cell activation [17].…”

“…Moreover, a crucial role in the LPS-mediated systemic shock is attributed to NK cells [35]. IL-10 is a potent immunosuppressive cytokine acting as a repressor by negatively regulating liver regeneration via a limiting inflammatory response and subsequently tempering hepatic STAT3 activation [18]. The IL-12 production is consecutively limited [17].…”