Corticosterone Enhances the Zinc and Interleukin-6-Mediated Induction of Metallothionein in Cultured Rat Hepatocytes

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Abstract
The regulation of metallothionein induction in cultured rat hepatocytes was investigated with Zn, hormones, cytokines and either the synthetic glucocorticoid, dexamethasone, or the endogenous rat glucocorticoid, corticosterone. A concentration-dependent increase was seen with Zn (two- to fivefold increase in 24 h, Zn 10–50 µmol/L). Dexamethasone at 1 µmol/L increased metallothionein synthesis by fourfold that of the controls. Maximal metallothionein concentrations of 17-fold the control value were seen with 50 µmol/L Zn and 1 µmol/L dexamethasone. Interleukin-6 (1 × 105 U/L) alone did not induce metallothionein but increased it 35–65% with Zn+dexamethasone. Like dexamethasone, corticosterone had a dose dependent effect on metallothionein and synergy with Zn and Zn+interleukin-6. Dexamethasone was ∼100 times more potent than corticosterone at 10–100 µmol/L. Physiological concentrations of corticosterone (1 µmol/L) when added alone, with Zn (10 µmol/L), and with Zn+interleukin-6 resulted in inductions of 2.2, 5.0 and 7.4-fold above the control cultures. Glucagon (1 µmol/L) had no independent effect but increased metallothionein by 31% and 33% with Zn(10 µmol/L)+dexamethasone (1 µmol/L) and Zn-dexamethasone+interleukin-6, respectively. There was no accumulation of metallothionein with interleukin-1β, tumor necrosis factor α or interferon γ (1 × 105 U/L) alone, but interleukin-1β and tumor necrosis factor α enhanced the response obtained with Zn+dexamethasone with and without interleukin-6. Insulin (100 U/L) alone, caused metallothionein accumulation and further enhanced the response seen with Zn+dexamethasone+interleukin-6+glucagon. No additional enhancement was seen with interleukin 1β+tumor necrosis factor α+interferon. The results demonstrate that concentrations of corticosterone in rats with experimental inflammation facilitate metallothionein induction with Zn and interleukin-6. The roles of other cytokines and glucagon demonstrate the multifactorial nature of metallothionein regulation.