Overproduction of liver sinusoidal cell (LCS) mediators in response to endotoxemia or gramnegative infection that follows tissue injury may contribute to hepatic dysfunction.
To better define the role of hepatocytederived acute-phase reactants in the regulation of sinusoidal cell mediator production following sequential insults, we tested the hypothesis that interleukin-6 (IL-6) prestimulation alters hepatocyte regulation of lipopolysaccharide (LPS)-stimulated sinusoidal cell tumor necrosis factor (TNF), IL-6, and nitric oxide production.
Hepatocytes and LSCs were isolated from Wistar rats, and in vitro responses were compared between LSCs alone and hepatocyte-LSC cocultures. Cocultures and LSCs alone were sequentially stimulated with IL-6 (5000 U/mL) then LPS (dose-response), and culture supernatants were analyzed for TNF (L929 cytolysis), IL-6 (7TD1 proliferation), and nitric oxide (Griess reaction). Induction of acute-phase protein synthesis by the stimulation of hepatocytes with IL-6 and dexamethasone (0.1 μmol/L) was assayed by methionine radiolabeling and SDS-PAGE (sodium dodecyl sulfate—polyacrylamide gel electrophoresis). Coculture levels of messenger RNA for TNF-α and IL-6 were examined by RNA extraction and reverse transcriptase polymerase chain reaction with specific primers.
Interleukin-6 and dexamethasone signal hepatocyte acute-phase protein synthesis. Prestimulation of cocultures, but not of LSCs alone, with IL-6 inhibits LPS-stimulated IL-6 and nitric oxide production significantly. Bioactivity of TNF is reduced to a lesser extent. Polymerase chain reaction analysis demonstrated similar levels of TNF and IL-6 message following sequential stimulation.
Interleukin-6–stimulated acute-phase hepatocytes limit LPS-stimulated coculture cytokine bioactivity and nitric oxide production. This hepatocyte response may provide a local counterregulatory mechanism to limit LSC-mediated injury.(Arch Surg. 1994;129:1166-1171)
Bankey P, Prager M, Geldon D, Taylor S, McIntyre K. Acute-Phase Hepatocytes Regulate Liver Sinusoidal Cell Mediator Production. Arch Surg. 1994;129(11):1166-1171. doi:10.1001/archsurg.1994.01420350064008