INTERLEUKIN-6 INHIBITS CORTICOSTEROID-BINDING GLOBULIN SYNTHESIS BY HUMAN HEPATOBLASTOMA-DERIVED (HEP G2) CELLS

Corticosteroid-binding globulin (CBG) belongs to the superfamily of se rine proteinase inhibitors which include alpha1-antitrypsin, alpha1-an ti-chymotrypsin, and T4-binding globulin. Interleukin-6 (IL-6), the ma in mediator of the acute phase phenomenon, increases alpha1-antitrypsi n and alpha1-antichymotrypsin synthesis and decreases T4-binding globu lin synthesis by human hepatoblastoma-derived (Hep G2) cells. This eff ect is predominantly at a transcriptional level. When Hep G2 cells wer e exposed to different concentrations of IL-6 for variable time interv als, IL-6 caused a dose- and time-dependent decrease in the amount of [S-35]methionine-labeled CBG immunoprecipitated in the culture medium. This effect could be greatly reduced by preincubation of IL-6 with it s neutralizing antibody and reversed by removing the cytokine from the culture medium. The secretion rate of CBG was not affected by cell ex posure to IL-6. CBG mRNA steady state levels were reduced; changes in mRNA were quantitatively similar to changes in secreted protein. Nucle ar run-off assays failed to show a change in the rate of transcription of the CBG gene. These data indicate that IL-6 diminishes CBG synthes is by Hep G2 cells acting at a posttranscriptional level, presumably t hrough a reduced stability of mRNA. In view of the role of IL-6 in the inflammatory process and other acute phase phenomena, these data sugg est that its effects on CBG synthesis might influence the bioavailabil ity of cortisol indirectly and play a role in regulating the homeostat ic process during these conditions.