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Molecular and Cellular Biology, April 2005, p. 2957-2968, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.2957-2968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

17ß-Estradiol Inhibits Inflammatory Gene Expression by Controlling NF-{kappa}B Intracellular Localization

Serena Ghisletti, Clara Meda, Adriana Maggi, and Elisabetta Vegeto*

Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy

Received 6 October 2004/ Returned for modification 5 November 2004/ Accepted 24 January 2005

Estrogen is an immunoregulatory agent, in that hormone deprivation increases while 17ß-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 {kappa}B (NF-{kappa}B) 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 E2 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-{kappa}B 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 I{kappa}-B{alpha} 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 (ER{alpha}) and not ERß 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.

* Corresponding author. Mailing address: Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Phone: 0039-02-50318290. Fax: 0039-02-50318284. E-mail: elisabetta.vegeto{at}unimi.it.

Molecular and Cellular Biology, April 2005, p. 2957-2968, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.2957-2968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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