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 kB (NF-kB) 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-kB 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 Ik-Ba 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 (ERa) and not ERb 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.
17beta-estradiol inhibits inflammatory gene expression by controlling NF-kB intracellular localization / S.M. Ghisletti, C. Meda, A.C. Maggi, E. Vegeto. - In: MOLECULAR AND CELLULAR BIOLOGY. - ISSN 0270-7306. - 25:8(2005 Apr), pp. 2957-2968.
|Titolo:||17beta-estradiol inhibits inflammatory gene expression by controlling NF-kB intracellular localization|
GHISLETTI, SERENA MARIA LUISA (Primo)
MEDA, CLARA (Secondo)
MAGGI, ADRIANA CATERINA (Penultimo)
VEGETO, ELISABETTA (Ultimo)
|Parole Chiave:||sex steroids ; intracellular receptors ; estrogen receptors|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||apr-2005|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1128/MCB.25.8.2957-2968.2005|
|Appare nelle tipologie:||01 - Articolo su periodico|