CORTICOSTEROID-BINDING GLOBULIN SYNTHESIS REGULATION BY CYTOKINES ANDGLUCOCORTICOIDS IN HUMAN HEPATOBLASTOMA-DERIVED (HEPG2) CELLS

Plasma corticosteroid-binding globulin (CBG) concentrations decrease d ramatically in patients with septic shock or burn injury. This decreas e suggests that mediators of the acute phase response, such as cytokin es and glucocorticoid hormones, might influence clearance as well as l iver synthesis of CBG in humans. The present study investigated the ef fects of interleukin-6 (IL-6), IL-1 beta, and dexamethasone on CBG syn thesis by a clone of human hepatoblastoma-derived (HepG2) cell line. I n culture medium from HepG2 cells, the immunoconcentration of CBG and the levels of CBG messenger ribonucleic acid (mRNA) were dose dependen tly decreased in the presence of IL-6 concentrations ranging from 0.1- 10 ng/mL. The percent decrease in CBG immunoconcentration was quantita tively similar to the percent decrease in CBG mRNA levels (29 +/- 6% a nd 39 +/- 15%, respectively, of control values). In contrast, and as e xpected, IL-6 dose dependently increased the mRNA levels (164 +/- 22% of control values) of alpha(1)-antitrypsin, a positive acute phase pro tein, but did not affect the immunoconcentration of sex hormone-bindin g globulin, another liver protein. Dexamethasone alone did not signifi cantly affect CBG secretion or mRNA levels, but did dose-dependently i ncrease tyrosine aminotransferase mRNA levels, which increased to 252 +/- 169 of the control values, However, in combination with IL-6, dexa methasone had a significant additive effect on IL-6 inhibition of CBG secretion and mRNAs in HepG2 cells. IL-1 beta dose-dependently stimula ted CBG secretion (156 +/- 10% of control values) with no significant effect on CBG mRNA levels. In addition, IL-1 beta significantly decrea sed the inhibitory effect of IL-6 on CBG secretion, but had no effect on the inhibitory effect of IL-6 on CBG mRNA levels. These results sug gest that IL-1 beta acts on the posttranslation processing and/or secr etion mechanisms of CBG in HepG2 cells. Together, the present results strongly support the hypothesis that the decrease in plasma CBG concen trations is associated with the increase in IL-6 and glucocorticoid le vels reported in patients with septic shock and burn injury.