Regulation of synthesis and secretion of major rat acute‐phase proteins by recombinant human interleukin‐6 (BSF‐2/1L‐6) in hepatocyte primary cultures

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Abstract
The regulation of the three major acute-phase proteins α2-macroglobulin, cysteine proteinase inhibitor and α1-antitrypsin by recombinant human interleukin-1β, recombinant human interleukin-6 and recombinant human tumor necrosis factor α was studied in rat hepatocyte primary cultures. Synthesis and secretion of the acute-phase proteins was measured after labeling with [35S]methionine and immunoprecipitation. Incubation of hepatocytes with interleukin-6 led to dose-dependent and time-dependent changes in the synthesis of the three major acute-phase proteins and albumin, similar to those occurring in vivoduring experimental inflammation. α2-Macroglobulin and cysteine proteinase inhibitor synthesis was induced 54-fold and 8-fold, respectively, 24 h after the addition of 100 units/ml interleukin-6. At the same time synthesis of the negative acute-phase protein albumin was reduced to 30% of controls. Half-maximal effects were achieved with 4 units interleukin-6/ml. Interleukin-1β had only a partial effect on the regulation of the four proteins studied: only a twofold stimulation of α2-macroglobulin and a 60% reduction of albumin synthesis were observed. Tumor necrosis factor α did not alter the synthesis of acute-phase proteins. The stimulation of α2-macroglobulin and cysteine proteinase inhibitor synthesis by interleukin-6 was inhibited by interleukin-1β in a dose-dependent manner. In pulse-chase experiments the effect of interleukin-1β, interleukin-6 and tumor necrosis factor α on the secretion of acute-phase proteins was examined. Interleukin-6 markedly accelerated the secretion of total proteins and α2-macroglobulin, whereas the secretion of cysteine proteinase inhibitor, α1 antitrypsin and albumin was not affected. The inhibition of N-glycosylation by tunicamycin abolished the effect of interleukin-6 on the secretion of α2-macroglobulin, indicating a possible role of interleukin-6 on N-glycosylation.