Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6-/- mice

Objective. Hepatic dysfunction is an important but poorly understood component of sepsis. In severe sepsis, liver dysfunction is characterized by cholestasis, steatosis, hepatocellular injury, impaired regeneration, a decreased response to the cytokine interleukin-6, and high mortality. To determine whether loss of interleukin-6 activity caused hepatic dysfunction and mortality, we induced sepsis in wild-type (interleukin-6 +/+) and interleukin-6 knockout (interieukin-6 -/-) mice. We hypothesized that sepsis in interleukin-6 -/- mice would increase cholestasis, steatosis, hepatocellular injury, and mortality and impair hepatocyte regeneration. Design: Randomized prospective experimental study. Setting. University medical laboratory. Subjects. Male adolescent C57BI6 interieukin-6 +/+ and interieukin-6 -/- mice. Interventions. Mild sepsis was induced using cecal ligation and single puncture (CLP). Severe, lethal sepsis was induced using cecal ligation and double puncture (2CLP). Some mice received recombinant human interleukin-6 at the time of CLP/ 2CLP. All animals were fluid resuscitated at the time of surgery and every 24 hrs thereafter. In survival cohorts, mortality at 16, 24, 48, and 72 hrs was recorded. In separate cohorts, surviving animals were killed at 24 and 48 hrs, and liver tissue was harvested. A separate cohort of mice received bromodeoxyuridine for detection of regeneration. Measurements and Main Results: 2CLP was 100% fatal within the first 12 hrs in interleukin-6 -/- mice. Mortality from 2CLP in interieukin-6 +/+ mice before 24 hrs was nil but was 90% by 72 hrs. At 72 hrs, CLP was 40% fatal in interieukin-6 +/+ mice but 90% in interleukin-6 -/- mice. CLP induced cholestasis, steatosis, and hepatocellular injury in interieukin-6 -/-, but not interleukin-6 +/+, mice. Regeneration was absent following CLP in interleukin-6 -/- animals but occurred in interleukin-6 +/+ mice. Early administration of recombinant human interleukin-6 did not reverse abnormalities in interleukin-6 -/- mice. Conclusions. The absence of interleukin-6 is an important determinant of hepatic dysfunction and mortality in sepsis.