CORTICOSTERONE ENHANCES THE ZINC AND INTERLEUKIN-6 - MEDIATED INDUCTION OF METALLOTHIONEIN IN CULTURED RAT HEPATOCYTES

The regulation of metallothionein induction in cultured rat hepatocyte s was investigated with Zn, hormones, cytokines and either the synthet ic 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 a t 1 mumol/L increased metallothionein synthesis by fourfold that of th e controls. Maximal metallothionein concentrations of 17-fold the cont rol value were seen with 50 mumol/L Zn and 1 mumol/L dexamethasone. In terleukin-6 (1 x 10(5) U/L) alone did not induce metallothionein but i ncreased it 35-65% with Zn+dexamethasone. Like dexamethasone, corticos terone had a dose dependent effect on metallothionein and synergy with Zn and Zn+interleukin-6. Dexamethasone was approximately 100 times mo re potent than corticosterone at 10-100 mumol/L. Physiological concent rations of corticosterone (1 mumol/L) when added alone, with Zn (10 mu mol/L), and with Zn+interleukin-6 resulted in inductions of 2.2, 5.0 a nd 7.4-fold above the control cultures. Glucagon (I mumol/L) had no in dependent effect but increased metallothionein by 31% and 33% with Zn( 10 mumol/L)+dexamethasone (1 mumol/L) and Zn-dexamethasone+ interleuki n-6, respectively. There was no accumulation of metallothionein with i nterleukin-1beta, tumor necrosis factor alpha or interferon gamma (1 x 10(5) U/L) alone, but interleukin-1beta and tumor necrosis factor ce enhanced the response obtained with Zn+dexamethasone with and without interleukin-6. Insulin (100 U/L) alone, caused metallothionein accumul ation and further enhanced the response seen with Zn+dexamethasone+int erleukin-6+glucagon. No additional enhancement was seen with interleuk in 1beta+tumor necrosis factor alpha+interferon. The results demonstra te that concentrations of corticosterone in rats with experimental inf lammation facilitate metallothionein induction with Zn and interleukin -6. The roles of other cytokines and glucagon demonstrate the multifac torial nature of metallothionein regulation.