Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD

J Clin Invest. 1999 Aug;104(4):503-13. doi: 10.1172/JCI7094.


Central to the bone-sparing effect of estrogen (E(2)) is its ability to block the monocytic production of the osteoclastogenic cytokine TNF-alpha (TNF). However, the mechanism by which E(2) downregulates TNF production is presently unknown. Transient transfection studies in HeLa cells, an E(2) receptor-negative line, suggest that E(2) inhibits TNF gene expression through an effect mediated by estrogen receptor beta (ERbeta). We also report that in RAW 264.7 cells, an E(2) receptor-positive murine monocytic line, E(2) downregulates cytokine-induced TNF gene expression by decreasing the activity of the Jun NH(2)-terminal kinase (JNK). The resulting diminished phosphorylation of c-Jun and JunD at their NH(2)-termini decreases the ability of these nuclear proteins to autostimulate the expression of the c-Jun and JunD genes, thus leading to lower production of c-Jun and JunD. The consequent decrease in the nuclear levels of c-Jun and JunD leads to diminished binding of c-Jun/c-Fos and JunD/c-Fos heterodimers to the AP-1 consensus sequence in the TNF promoter and, thus, to decreased transactivation of the TNF gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Cell Line
  • DNA Primers / genetics
  • Down-Regulation / drug effects
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • HeLa Cells
  • Humans
  • Interleukin-1 / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases*
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / biosynthesis*
  • Proto-Oncogene Proteins c-jun / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Transcription Factor AP-1 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / pharmacology


  • DNA Primers
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Interleukin-1
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, Estrogen
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Estradiol
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases