17β-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization

Serena Ghisletti, Clara Meda, Adriana Maggi, Elisabetta Vegeto

Research output: Contribution to journalArticle

Abstract

Estrogen is an immunoregulatory agent, in that hormone deprivation increases while 17β-estradiol (E2) administration blocks the inflammatory response; however, the underlying mechanism is still unknown. The transcription factor p65/relA, a member of the nuclear factor κB (NF-κB) family, plays a major role in inflammation and drives the expression of proinflammatory mediators. Here we report a novel mechanism of action of E2 in inflammation. We observe that in macrophages E 2 blocks lipopolysaccharide-induced DNA binding and transcriptional activity of p65 by preventing its nuclear translocation. This effect is selectively activated in macrophages to prevent p65 activation by inflammatory agents and extends to other members of the NF-κB family, including c-Rel and p50. We observe that E2 activates a rapid and persistent response that involves the activation of phosphatidylinositol 3-kinase, without requiring de novo protein synthesis or modifying Iκ-Bα degradation and mitogen-activated protein kinase activation. Using a time course experiment and the microtubule-disrupting agent nocodazole, we observe that the hormone inhibits p65 intracellular transport to the nucleus. This activity is selectively mediated by estrogen receptor alpha (ERα) and not ERβ and is not shared by conventional anti-inflammatory drugs. These results unravel a novel and unique mechanism for E2 anti-inflammatory activity, which may be useful for identifying more selective ligands for the prevention of the inflammatory response.

Original languageEnglish
Pages (from-to)2957-2968
Number of pages12
JournalMolecular and Cellular Biology
Volume25
Issue number8
DOIs
Publication statusPublished - Apr 2005

Fingerprint

Transcription Factor RelA
Estrogen Receptor alpha
Estradiol
Anti-Inflammatory Agents
Macrophages
Phosphatidylinositol 3-Kinase
Hormones
Inflammation
Nocodazole
Gene Expression
Mitogen-Activated Protein Kinases
Microtubules
Lipopolysaccharides
Estrogens
Ligands
DNA
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

17β-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. / Ghisletti, Serena; Meda, Clara; Maggi, Adriana; Vegeto, Elisabetta.

In: Molecular and Cellular Biology, Vol. 25, No. 8, 04.2005, p. 2957-2968.

Research output: Contribution to journalArticle

Ghisletti, Serena ; Meda, Clara ; Maggi, Adriana ; Vegeto, Elisabetta. / 17β-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 8. pp. 2957-2968.
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