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

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 mumol/L). Dexamethasone at 1 mumol/L increased metallothionein synthesis by fourfold that of the controls. Maximal metallothionein concentrations of 17-fold the control value were seen with 50 mumol/L Zn and 1 mumol/L dexamethasone. Interleukin-6 (1 x 10(5) 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 approximately 100 times more potent than corticosterone at 10-100 mumol/L. Physiological concentrations of corticosterone (1 mumol/L) when added alone, with Zn (10 mumol/L), and with Zn+interleukin-6 resulted in inductions of 2.2, 5.0 and 7.4-fold above the control cultures. Glucagon (1 mumol/L) had no independent effect but increased metallothionein by 31% and 33% with Zn(10 mumol/L)+dexamethasone (1 mumol/L) and Zn-dexamethasone+interleukin-6, respectively. There was no accumulation of metallothionein with interleukin-1 beta, tumor necrosis factor alpha or interferon gamma (1 x 10(5) U/L) alone, but interleukin-1 beta and tumor necrosis factor alpha 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 1 beta+tumor necrosis factor alpha+interferon. The results demonstrate that concentrations of corticosterone in rats with experimental inflammation facilitate metallothionein induction with Zn and interleukin-6.(ABSTRACT TRUNCATED AT 250 WORDS)