Selective Estrogen Receptor-β Agonists Repress Transcription of Proinflammatory Genes

Čvoro, Aleksandra; Tatomer, Deirdre C.; Tee, Meng Kian; Zogovic, Tatjana; Harris, Heather A.; Leitman, Dale C.

doi:10.4049/jimmunol.180.1.630

Cited by 124 publications

(65 citation statements)

References 62 publications

(69 reference statements)

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“…Es- tradiol exerts activity through two distinct estrogen receptors (estrogen receptor ␣ [ER␣] and ER␤) that populate different tissues and cell lines (56). Estrogen receptor ␤ has previously been shown to have anti-inflammatory activity with repression of multiple cytokines in immune cells, whereas ER␣ is more associated with anabolic activity in the female mammary gland and reproductive tract (57). Which receptor and which pathway are more important for producing asymptomatic S. pyogenes carriage are unknown, but the murine vaginal carriage model could provide valuable insight into estradiol and its link to carriage and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Murine Vaginal Colonization Model for Investigating Asymptomatic Mucosal Carriage of Streptococcus pyogenes

et al. 2013

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While many virulence factors promoting Streptococcus pyogenes invasive disease have been described, specific streptococcal factors and host properties influencing asymptomatic mucosal carriage remain uncertain. To address the need for a refined model of prolonged S. pyogenes asymptomatic mucosal colonization, we have adapted a preestrogenized murine vaginal colonization model for S. pyogenes. In this model, derivatives of strains HSC5, SF370, JRS4, NZ131, and MEW123 established a reproducible, asymptomatic colonization of the vaginal mucosa over a period of typically 3 to 4 weeks' duration at a relatively high colonization efficiency. Prior treatment with estradiol prolonged streptococcal colonization and was associated with reduced inflammation in the colonized vaginal epithelium as well as a decreased leukocyte presence in vaginal fluid compared to the levels of inflammation and leukocyte presence in non-estradiol-treated control mice. The utility of our model for investigating S. pyogenes factors contributing to mucosal carriage was verified, as a mutant with a mutation in the transcriptional regulator catabolite control protein A (CcpA) demonstrated significant impairment in vaginal colonization. An assessment of in vivo transcriptional activity in the CcpA ؊ strain for several known CcpA-regulated genes identified significantly elevated transcription of lactate oxidase (lctO) correlating with excessive generation of hydrogen peroxide to self-lethal levels. Deletion of lctO did not impair colonization, but deletion of lctO in a CcpA ؊ strain prolonged carriage, exceeding even that of the wild-type strain. Thus, while LctO is not essential for vaginal colonization, its dysregulation is deleterious, highlighting the critical role of CcpA in promoting mucosal colonization. The vaginal colonization model should prove effective for future analyses of S. pyogenes mucosal colonization. The Gram-positive pathogen Streptococcus pyogenes, or group A streptococcus, is responsible for a wide variety of clinical manifestations ranging from the relatively benign and superficial otitis media, impetigo, and pharyngitis to less common and more invasive conditions, including necrotizing fasciitis and toxic shock syndrome, in addition to the postinfectious complications rheumatic fever and glomerulonephritis (1). The ability to produce such a diversity of infections in so many different tissue compartments is testament to the extensive plasticity of the S. pyogenes transcriptome and an abundance of secreted virulence factors (2). While not considered normal human flora, S. pyogenes can be identified as a colonizer of mucosal surfaces of the oropharynx, rectum, and vaginal mucosa, and a prolonged asymptomatic carriage state can develop (3-7). How S. pyogenes carriage exists on a mucosal surface without inducing disease is poorly understood, but the issue is significant in terms of gaining an improved understanding of host-pathogen interactions and the regulation of mucosal immunity. Furthermore, asymptomatic oropharyngeal carri...

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Section: Discussionmentioning

confidence: 99%

Murine Vaginal Colonization Model for Investigating Asymptomatic Mucosal Carriage of Streptococcus pyogenes

et al. 2013

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“…The shorter ERb1 protein may be more stable than the long form as it is potentially missing the binding site for the ubiquitin ligase, carboxyl terminus of HSC70-interacting protein (CHIP), required for inducing ERb1 proteasomal degradation (Tateishi et al 2006). Functional differences between the long and short forms of ERb1 have been described, in particular associated with anti-inflammatory activities of ERb1 (Bhat et al 1998, Tateishi et al 2006, Cvoro et al 2008, Saijo et al 2011. Furthermore, it has been shown that Pescadillo ribosomal biogenesis factor 1 (PES1) differentially affects ERb1 and ERa at a posttranslational level and may, in part, be responsible for the altered ratios of ERa/ERb seen consistently during breast tumorigenesis (Cheng et al 2012, Thomas & Gustafsson 2012.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

A bi-faceted role of estrogen receptor β in breast cancer

Leygue¹,

Murphy²

2013

Endocrine-Related Cancer

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Despite over 15 years of research, the exact role, if any, played by estrogen receptor b (ERb) in human breast cancer remains elusive. A large body of data both in vitro and in vivo supports its role as an antiproliferative, pro-apoptotic factor especially when co-expressed with ERa. However, there is a smaller body of data associating ERb with growth and survival in breast cancer. In clinical studies and most often in cell culture studies, the pro-growth and prosurvival activity of ERb occurs in ERa-negative breast cancer tissue and cells. This bi-faceted role of ERb is discussed in this review.

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“…Les estrogènes jouent un rôle complexe dans l'inflammation in vitro et in vivo (Straub, 2007, pour revue ;Cvoro et al, 2008).…”

Section: Les Récepteurs Nucléaires Aux Estrogènes : Reα Et Reβunclassified

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

et al. 2012

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Titre : La 7β-hydroxy-épiandrostérone dans des modèles in vitro de cancer du sein : effets anti-estrogéniques et rôle des récepteurs des estrogènes. La 7β-hydroxy-épiandrostérone, stéroïde endogène dérivant de la DHEA, présente des propriétés antiinflammatoires. En effet, elle module la voie des prostaglandines (PGs) en inhibant la production de la PGE2 pro-inflammatoires et en augmentant la production de la 15-Deoxy-∆ 12,14 -PGJ2 cyto-protectrice in vivo et in vitro. Les faibles doses de 7β-hydroxy-épiandrostérone (1nM, 10nM, 100nM) pour lesquelles ces effets sont observés, suggèrent une liaison à un récepteur spécifique. L'inflammation et la production des PGs jouent un rôle important dans le développement et la prolifération des tumeurs mammaires estrogéno-dépendantes. Le 17β-estradiol (E2), en se fixant sur les récepteurs des estrogènes (REs), induit la production de PGE2 et la prolifération cellulaire dans ces cellules tumorales. De ce fait, notre objectif était de tester les effets de la 7β-hydroxy-épiandrostérone sur la prolifération (comptage avec exclusion au bleu trypan), le cycle cellulaire et l'apoptose (cytométrie de flux) dans les lignées cellulaires de cancer du sein MCF-7 (REα+, REβ+, GPR30+) et MDA-MB-231 (REα-, REβ+, GPR30+) et d'identifier une(des) cible(s) potentielle(s) dans ces cellules (transactivation) et dans des cellules négatives pour les REs nucléaires SKBr3 (GPR30+) (études de prolifération). Cette étude a montré que la 7β-hydroxy-épiandrostérone exerce des effets anti-estrogéniques dans les cellules MCF-7 et MDA-MB-231 associés à une inhibition de la prolifération et un arrêt du cycle cellulaire. Les études de transactivation et de prolifération avec les agonistes spécifiques des REs ont montré une interaction avec le REβ. De plus, les résultats des études de proliférations sur les trois lignées cellulaires suggèrent que la 7β-hydroxy-épiandrostérone pourrait également interagir avec le GPR30. Ces résultats indiquent que ce stéroïde androgène agit comme un anti-estrogène. De plus, c'est la première fois qu'un stéroïde androgène à faible dose montre une action anti-proliférative dans des lignées de cancers du sein. De études ultérieures restent à réaliser afin de mieux comprendre ces effets observés. Mots clés : 7β-hydroxy-épiandrostérone, récepteurs des estrogènes, lignées de carcinomes mammaires, prolifération, transactivationThe DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines 7β-hydroxy-epiandrosterone, an endogenous androgenic derivative of DHEA, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-∆ 12,14 -PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7β-hydroxy-epiandrosterone (1-100 nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogendependent mammary cancers. Estrogen induced PGE2 ...

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Selective Estrogen Receptor-β Agonists Repress Transcription of Proinflammatory Genes

Cited by 124 publications

References 62 publications

Murine Vaginal Colonization Model for Investigating Asymptomatic Mucosal Carriage of Streptococcus pyogenes

Murine Vaginal Colonization Model for Investigating Asymptomatic Mucosal Carriage of Streptococcus pyogenes

A bi-faceted role of estrogen receptor β in breast cancer

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

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