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

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. Copyright © 1988, Wiley Blackwell. All rights reserved