Requirement for cooperative interaction of interleukin-6 responsive element type 2 and glucocorticoid responsive element in the synergistic activation of mouse metallothionein-I gene by interleukin-6 and glucocorticoid

Toxicol Appl Pharmacol. 1998 Jul;151(1):143-51. doi: 10.1006/taap.1998.8452.


Metallothionein (MT)-inducing activity of interleukin (IL)-6 depends on the presence of glucocorticoid in hepatic cells. The synergistic action of IL-6 and glucocorticoid was observed in the transcriptional activation of the mouse MT (mMT)-I gene. We found that a 281-bp promoter was sufficient for IL-6 and glucocorticoid stimulation. Our inspection of this region revealed the putative type 1 and 2 IL-6 responsive elements (REs). Functional analyses of these regions were performed using luciferase reporter constructs, and it was observed that the type 2 IL-6RE exerted the major response to the IL-6 signal. The transcriptional factor binding to type 1 IL-6RE, nuclear factor-IL-6, hardly contributed to the activation of the mMT-I promoter by IL-6 and glucocorticoid. A glucocorticoid responsive element (GRE) was also required for the synergistic activation by IL-6 and glucocorticoid. Interestingly, this synergism was not observed when the type 2 IL-6RE and the GRE were kept apart. Therefore, the synergistic activation of the mMT-I gene by IL-6 and glucocorticoid may require not only that signal transducers and activators 3 (Stat3) and the glucocorticoid receptor (GR) bind to their respective responsive elements, but also that Stat3 and the GR physically interact with one another.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / metabolism
  • Animals
  • DNA-Binding Proteins / metabolism*
  • Drug Synergism
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology*
  • Interleukin-6 / pharmacology*
  • Metallothionein / biosynthesis*
  • Metallothionein / genetics
  • Mice
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics
  • Rats
  • STAT3 Transcription Factor
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured


  • Acute-Phase Proteins
  • DNA-Binding Proteins
  • Glucocorticoids
  • Gmeb1 protein, mouse
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Stat3 protein, rat
  • Trans-Activators
  • Transcription Factors
  • Metallothionein