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PubMed · 7526821

Acute-phase hepatocytes regulate liver sinusoidal cell mediator production.

P Bankey·M Prager·D Geldon·S Taylor·K McIntyre
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Abstract

BACKGROUND: Overproduction of liver sinusoidal cell (LCS) mediators in response to endotoxemia or gram-negative infection that follows tissue injury may contribute to hepatic dysfunction. OBJECTIVE: To better define the role of hepatocyte-derived 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. METHODS: 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 mumol/L) was assayed by methionine radiolabeling and SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Coculture levels of messenger RNA for TNF-alpha and IL-6 were examined by RNA extraction and reverse transcriptase polymerase chain reaction with specific primers. RESULTS: 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. CONCLUSIONS: 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.

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Acute-Phase ProteinsAcute-Phase ReactionAnalysis of VarianceAnimalsIn Vitro TechniquesInflammation MediatorsInterleukin-6LiverNitric OxidePolymerase Chain ReactionRatsRats, WistarTumor Necrosis Factor-alphaJournal Article

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P Bankey, M Prager, D Geldon, S Taylor, K McIntyre. 1994. Acute-phase hepatocytes regulate liver sinusoidal cell mediator production.. https://doi.org/10.1001/archsurg.1994.01420350064008

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