Metallothionein induction by restraint stress: role of glucocorticoids and IL-6

Cytokine. 2000 Jun;12(6):791-6. doi: 10.1006/cyto.1999.0629.


Restraint stress increased liver metallothionein-I (MT-I) mRNA and MT-I+II protein levels. The glucocorticoid receptor antagonist RU 486 decreased this response. In contrast, adrenalectomy only decreased MT-I+II protein levels. Moreover, corticosterone or progesterone did not reverse the effect of RU 486. These results suggest that glucocorticoids are important for MT-I+II protein synthesis but not for MT-I mRNA accumulation during restraint stress, and that other factors must be involved in this process. Interleukin-6 (IL-6) deficient mice showed a significant decrease of restraint stress-induced liver MT-I mRNA levels (approximately 30% of IL-6+/+ mice) up to approximately 4-5 hours after the onset of stress. Western blotting of hepatic nuclear proteins showed that the IL-6 responsive transcription factor Stat3, which has been shown to mediate MT induction by inflammation, was also activated by restraint stress. Results after extended periods of restraint stress indicate that IL-6 participates early and transiently in the process. The analysis of the expression of the acute phase plasma protein serum amyloid A suggests that restraint stress elicits an acute phase response similar to that caused by inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenalectomy
  • Animals
  • Corticosterone / pharmacology
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation* / drug effects
  • Glucocorticoids / physiology*
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Kinetics
  • Metallothionein / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mifepristone / pharmacology
  • Progesterone / pharmacology
  • RNA, Messenger / genetics
  • Restraint, Physical
  • STAT3 Transcription Factor
  • Stress, Psychological / immunology
  • Stress, Psychological / physiopathology*
  • Time Factors
  • Trans-Activators / metabolism
  • Transcription, Genetic


  • DNA-Binding Proteins
  • Glucocorticoids
  • Interleukin-6
  • RNA, Messenger
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Mifepristone
  • Progesterone
  • Metallothionein
  • Corticosterone