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

Hellenic National Diabetes Center Athens, Greece

George P. Chrousos and Dimitris A. Papanicolaou

Developmental Endocrinology Branch National Institute of Child Health and Human Development, NIH Bethesda, Maryland

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.

View larger version (14K): [in this window] [in a new window]   Figure 1. 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.

Footnotes

Address correspondence to: Constantine Tsigos, M.D., Hellenic National Diabetes Center, 3 Ploutarchou Street, 106 75 Athens, Greece.

Received April 23, 1998.

References

1. Rosner W. 1990 The functions of corticosteroid-binding globulin and sex-hormone binding globulin: recent advances. Endocr Rev. 11:80–91.[CrossRef][Medline]
2. Emptoz-Bonneton A, Crave JC, Lejeune H, Brebart C, Pugeat M. 1997 Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells. J Clin Endocrinol Metab. 82:3758–3762.[Abstract/Free Full Text]
3. Underhill DA, Hammond GL. 1995 cis-Regulatory elements within the proximal promoter of the rat gene encoding corticosteroid-binding globulin. Gene. 162:205–211.[CrossRef][Medline]
4. Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. 1997 Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab. 82:4167–4170.[Abstract/Free Full Text]
5. Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos GP. 1997 Dose-effects of recombinant human interleukin-6 on anterior pituitary hormone secretion and thermogenesis. Neuroendocrinology. 66:54–62.[Medline]
6. Pugeat MM, Nisula BC, Dunn JF. 1981 Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 53:69–75.[Abstract]
7. Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ. 1992 Systemic cytokine response after major surgery. Br J Surg. 79:759–760.
8. Evans SW, Whicher JT. 1993 The cytokines: physiological and pathophysiologic aspects. Adv Clin Chem. 30:1–88.[Medline]

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