Prolonged Suppression of Corticosteroid-Binding Globulin by Recombinant Human Interleukin-6 in Man

Corticosteroid-binding globulin (CBG), a glucoprotein of hepatic origin, binds cortisol and modifies its bioavailability (1). Interleukin-6 (IL-6) dose-dependently inhibits CBG messenger RNA expression and protein secretion by hepatoblastoma-derived (HepG2) cells (2). This is consistent with the presence of a nuclear factor-IL-6-binding site in the rat CBG gene promoter, also conserved in the promoter of the human CBG gene (3). These findings suggest that CBG is a negative acute phase reactant protein. We recently reported the results of a dose-response study of single subcutaneous injections of recombinant human IL-6 on pituitary hormone production and glucose metabolism in healthy male volunteers (4, 5). We hereby provide evidence from these volunteers that supports the inhibitory effect of IL-6 on CBG production. We measured CBG (6), cortisol, and the positive acute phase reactant C-reactive protein (CRP) at baseline, then at 24 h, 48 h, and 7 days after the IL-6 injection in three volunteers who received 0.3 μg/kg of IL-6, a dose that did not activate the hypothalamic-pituitary-adrenal (HPA) axis and in three volunteers who received 3.0 μg/kg of IL-6, a dose that strongly stimulated the HPA axis (4). Plasma IL-6 levels reached a peak of 22 ± 5 pg/mL and 290 ± 38 pg/mL for the two doses respectively, between 2 and 4 h after the injection, and returned to baseline by 24 h in both groups. While the 0.3 μg/kg dose did not appreciably influence plasma CBC levels, the 3.0 μg/kg dose caused a significant and persistent decrease in CBC levels that lasted at least 48 h, but returned to baseline by 7 days (Fig. 1).The corresponding CRP levels showed a mirror image response, increasing significantly by 24 h (from 0.77 ± 0.06 mg/dL to 9.8 ± 1.01 mg/dL, P < 0.01), remaining elevated at 48 h (6.0 ± 1.24, P < 0.05 vs. baseline) and returning to normal by 7 days (0.75 ± 0.05 mg/dL). Cortisol levels, despite the dramatic response observed during the first 4 h after the IL-6 injection (4), were at baseline by 24 h and remained so thereafter. It is of note that the plasma IL-6 concentrations reached after the 3.0μ g/kg dose are within the range of plasma IL-6 concentrations previously reported in septic patients or during acute trauma and surgery (7, 8) and that CBG levels are dramatically decreased in such patients, suggesting that hepatic production of CBG is inhibited. The in vitro data of Emptoz-Bonneron et al. (2) and our findings in healthy humans suggest that IL-6 is a regulator of CBG production and, hence, a determinant of cortisol bioavailability. Mean ± se plasma CBG responses to the two doses (0.3 and 3.0 μg/kg) of recombinant human IL-6 administration. * P < 0.02 by paired t-test.