Conventional Hair Loss meets Alternative views: The role of inflammation in the gene expression and activation of sex hormone receptor sites

Inflammation and Sex Steroid Receptors: A Motif for Change

Jan J. Brosens1,
Eric W.-F. Lam2,
Malcolm G. Parker1, Corresponding author contact information, E-mail the corresponding author

1 Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom
2 Department of Oncology, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom

Available online 9 February 2006.

http://dx.doi.org/10.1016/j.cell.2006.01.023, How to Cite or Link Using DOI
Cited by in Scopus (2)

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Homeostasis in reproductive tissues requires integration of hormonal and inflammatory signals. In this issue of Cell, Zhu et al. (2006) discover that proinflammatory signals switch repressed steroid hormonereceptors into transcriptional activators by targeting TAB2, an adaptor protein that tethers corepressors. These findings have implications for the treatment of endocrine-resistant cancers.
Main Text

Inflammation plays a crucial role in the protective response against infections as well as in tissue remodeling in many physiological processes, such as reproduction. The precise control of inflammation is essential for the prevention of chronic inflammatory disorders as well as for inhibiting the exacerbation or progression of diseases such as atherosclerosis and cancer. Natural and synthetic steroids can target distinct steps in the inflammatory process, and considerable progress has been made in elucidating the molecular mechanisms involved. Conversely, relatively little is known about the impact of inflammatory molecules on steroid hormone action. In this issue of Cell, Zhu et al. (2006) report that the proinflammatory cytokine interleukin-1β (IL-1β) reverses the inhibitory effects of sexhormonereceptor antagonists. This surprising finding may have profound implications for the treatment of certain hormone-dependent cancers. In fact, their observations may be of broader physiological significance as the authors also show that IL-1β reverses the inhibitory effects of natural steroids, more specifically 17-β-estradiol (E2), in MCF7 breast cancer cells.

The sex steroids (estrogens, androgens, and progestins) are not only indispensable for reproduction but also control many diverse physiological functions in other tissues. They are also implicated in the initiation and progression of many benign and malignant disease processes, perhaps most prominently in breast and prostate cancer. Their action is mediated by specific receptors that are members of the nuclear receptor family of ligand-dependent transcription factors. Consequently selective antagonists for the estrogen receptor and the androgen receptor are widely used for the prevention and treatment of breast and prostate cancers, respectively. Activation or repression of gene transcription by nuclear receptors is dependent on the recruitment of coactivators or corepressors that form scaffolds for the assembly of chromatin remodeling enzyme complexes. The ability of steroid hormones to control the transcription of distinct gene networks in target cells seems to reflect, in part, the recruitment of different chromatin remodeling complexes. The generation of diverse physiological responses, however, requires further regulation of steroid receptors through crosscoupling with distinct signaling pathways that vary according to the cell type and microenvironment. Deciphering the interactions between these pathways is essential for understanding the cellular responses controlled by steroid hormones in physiological and pathological processes.

Previous observations by Rosenfeld and coworkers have demonstrated that IL-1β causes nuclear export of a specific N-CoR corepressor complex (Baek et al., 2002). A number of laboratories have established that this corepressor is recruited to sex steroid receptors in the presence of synthetic antagonists to prevent transcription from target genes ( [Jackson et al., 1997] and [Smith et al., 1997]). Zhu et al. (2006) have now discovered that IL-1β is capable of switching these antagonists into agonists and thereby activating, rather than repressing, target gene transcription. A series of experiments led the authors to focus on the function of a nucleocytoplasmic shuttling adaptor protein called TAB2 (Takaesu et al., 2000). They demonstrate that TAB2 binds to an L/HX7LL motif in the N-terminal domain of sex steroid receptors. This domain is absent in other nuclear receptors. In response to IL-1β signals, MEKK1 (MAPK kinase kinase 1), an essential upstream signaling component of the mitogen-activated protein kinase (MAPK) cascade, is recruited to the N-CoR corepressor complex by coactivators, such as Tip60, to phosphorylate TAB2. Once phosphorylated by MEKK1, TAB2 dissociates from the sex steroid hormonereceptors and tethers N-CoR away from receptor bound target genes, leading to nuclear export of the N-CoR corepressor complex, as previously reported (Baek et al., 2002). As a consequence, bicalutamide, an anti-androgen, no longer blocks the transcriptional activity of the androgen receptor but, surprisingly, stimulates it, presumably as a consequence of coactivator recruitment (see Figure 1). The ability of IL-1β to convert antagonists into agonists was also found for tamoxifen, an estrogen receptor antagonist, and mifepristone (RU486), a progesterone receptor antagonist.

Full-size image

Figure 1. IL-1β Signaling Reverses Transcriptional Repression by Steroid Receptor AntagonistsThe androgen receptor (blue) contains an N-terminal activation function 1 (AF-1) domain, a C-terminal activation function 2 (AF-2) domain, and a DNA binding domain (DBD), which binds to the androgen-responsive element (ARE) of target genes. Upon binding of the specific androgen antagonist, bicalutamide (B), AR associates with a nuclear receptor corepressor (N-CoR), which recruits histone deacetylases (HDACs) that repress gene transcription. The proinflammatory cytokine IL-1β activates MEKK1 resulting in phosphorylation of TAB2. Upon phosphorylation, TAB2 changes its conformation, increases its affinity for N-CoR, and relocates to the cytoplasm thereby tethering N-CoR away from AR, culminating in derepression of target gene expression. The subsequent recruitment of coactivators (CoAs) together with histone acetyltransferases (HATs) to AR results in target gene activation.

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Breast and prostate tumors are commonly infiltrated by macrophages. High levels of colony-stimulating factor 1 (CSF-1), a cytokine involved in recruiting and activating macrophages, is associated with poor prognosis and resistance to endocrine therapy (McDermott et al., 2002). The authors not only present an attractive paradigm to explain these clinico-pathological observations, they also demonstrate that the ability of IL-1β to switch antagonists to agonists can be blocked by disrupting the interaction between TAB2 and the L/HX7LL motif of sexhormonereceptors. This approach could potentially be exploited for the prevention or treatment of endocrine-resistant cancers. However, multiple mechanisms are thought to contribute to the acquisition of hormone resistance in cancer, including increased circulating sexhormone levels, hormone hypersensitivity, increased growth factor signaling, downregulation of corepressors, upregulation of coactivators, and suppression or loss of nuclear receptor expression. On the other hand, it is intriguing to note that ERβ, the only sexhormonereceptor that seems to lack a conserved L/HX7LL motif, may not have a major role in the development of tamoxifen resistance (Chen et al., 2005). Although tamoxifen is an effective ERα antagonist in breast cancer cells, it can exert agonistic activity in cells of the uterus, thereby increasing the risk of endometrial cancer. It will therefore be interesting to determine if these opposing effects of tamoxifen in vivo can be linked to tissue-specific differences in the number and activation status of local macrophages.

The observation that the sexhormonereceptors are inextricably linked to inflammatory mediators through an evolutionarily conserved N-terminal L/HX7LL motif may be of particular relevance to reproduction. Local inflammation in response to tissue accumulation of macrophages and other immune cells precedes every major reproductive event in the ovaries and uterus, from ovulation to implantation and menstruation ( [Jabbour et al., 2005] and [Wu et al., 2004]). Macrophages are important in these events because of their ability to execute diverse functional activities including phagocytosis, matrix degradation and tissue remodeling, and production of growth factors, cytokines, and chemokines. However, the observations of Zhu et al. (2006) suggest that these infiltrating cells may also provide the cellular signals for local expression of genes otherwise repressed by sexhormonereceptors. Using breast cancer cells, the authors demonstrate that IL-1β reverses E2-mediated repression of a limited number of genes, some with relevance to reproduction, by interfering with the N-CoR/TAB2/ERα complex. Functional “switching” of cellular responses to natural hormones by inflammatory cytokines is an attractive model with direct relevance to various reproductive events. For instance, uterine quiescence during pregnancy is dependent upon progesterone-mediated repression of genes that encode proteins associated with muscle contraction. However, transition to muscle contractions during labor does not require a fall in circulating progesterone levels but is invariably preceded by an influx of immune cells into the myometrium and cervix and local expression of inflammatory cytokines (Mendelson and Condon, 2005). Preterm labor is now widely considered to be an inflammatory disease that accounts for the majority of neonatal deaths. Hence, by lifting the veil covering a hitherto unrecognized molecular mechanism, Zhu et al. (2006) have set new challenges. None of these challenges is more important than translating this new molecular information into more effective therapies for hormone-dependent cancers and common reproductive disorders

This study outlines how inflammation can interact with mutiple parameters to activate different sex hormone binding sites and functions. This brings up the possibility that upregulated androgen sites in males with hair loss is a result of inflammation, just as it is a cause of inflammation.

Interleukin-6 Induces Androgen Responsiveness in Prostate Cancer Cells through Up-Regulation of Androgen Receptor Expression1

Din-Lii Lin,
Mary C. Whitney,
Zhi Yao, and
Evan T. Keller2

+ Author Affiliations

Unit for Laboratory Animal Medicine [D-L. L., M. C. W., E. T. K.], Department of Pathology [E. T. K.], Program in Cellular and Molecular Biology [E. T. K.], and Institute of Gerontology [E. T. K.], University of Michigan, Ann Arbor, Michigan 48109, and Department of Immunology, Tianjin Medical University, Tianjin, China 300203 [Z.Y.]

Abstract

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879n-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling▿

Tatsuo Kanda1,
Robert Steele1,
Ranjit Ray2,3, and
Ratna B. Ray1,2,3,*

+ Author Affiliations

1Departments of Pathology
2Internal Medicine
3Cancer Center, Saint Louis University, St. Louis, Missouri 63104

ABSTRACT

Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male-dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross talk with the androgen receptor (AR) signaling pathway for promotion of carcinogenesis. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of the Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of AR in liver and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. Together, our results suggest that HCV core protein acts as a positive regulator in AR signaling, providing further insight into oncogenic potential in the development of HCC in HCV-infected individuals.

anthonyspencer54 wrote:Is this latter study actually saying that the interleukin can have all the effects of the androgen without there actually being androgen present? If this applies to other IL, does this indicate that we could be experiencing the effects of hormones but our actual levels might not be proportionate?

Could you quote the exact part of the study your referring to?

And overall, A > R, do you feel that an inflammatory state in general will increase AR activity? Obviously the presence of actual androgen has an effect, but I'm trying to figure out what the takeaway should really be. I didn't see anything that pointed to activation of the sex hormone receptor by an actual steroid hormone increasing inflammatory markers.

I do feel that, yeah, based on observation and a lot of different studies. The takeaway to all this really is simple, inflammation from any variable, provided its the right cytokine, can induce epigenetic changes that make us more sensetive to specific hormones, in this case sex hormones.

Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways*

Takeshi Ueda,
Nicholas Bruchovsky and
Marianne D. Sadar‡

+ Author Affiliations

From the Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada

Abstract

The androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. However, non-androgenic pathways have also been shown to activate the AR. The mechanism of cross-talk between the interleukin-6 (IL-6) and AR signal transduction pathways was investigated in LNCaP human prostate cancer cells. IL-6 induced several androgen-response element-driven reporters that are dependent upon the AR, increased the phosphorylation of mitogen-activated protein kinase (MAPK), and activated the AR N-terminal domain (NTD). Inhibitors to MAPK and JAK decreased the IL-6-induced phosphorylation of MAPK and activation of the AR NTD. Immunoprecipitation and transactivation studies showed a direct interaction between amino acids 234–558 of the AR NTD and STAT3 following IL-6 treatment of LNCaP cells. These results demonstrate that activation of the human AR NTD by IL-6 was mediated through MAPK and STAT3 signal transduction pathways in LNCaP prostate cancer cells.

Influence of interleukin-1alpha on androgen receptor expression and cytokine secretion by cultured human dermal papilla cells.
Boivin WA, Jiang H, Utting OB, Hunt DW.
Source

Scientific Affairs: Dermatology, QLT Inc., 887 Great Northern Way, Vancouver, British Columbia, Canada.
Abstract

Dermal papilla cells (DPC) control the growth character of the hair follicle through their elaboration of mitogenic factors and extracellular matrix components. Further, the dermal papilla is a primary site of androgen action in the hair follicle. Interleukin-1alpha (IL-1alpha) is prominent in skin wounding and inflammatory responses although regarded as a negative hair growth regulator. We studied the effect of IL-1alpha and the potent androgen 5alpha-dihydrotestosterone (DHT) on the expression of the androgen receptor (AR) and various factors secreted by cultured human temporal scalp DPC. IL-1alpha triggered cellular changes consistent with nuclear factor-kappaB pathway activation as well as reduced AR mRNA and protein expression levels for DHT-stimulated DPC. This cytokine also increased DPC supernatant keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. IL-1alpha did not influence DPC supernatant levels of transforming growth factor-beta1, a negative hair growth regulator. The stimulatory effect of IL-1alpha on DPC VEGF, GM-CSF, KGF, and IL-8 expression was also evident at the mRNA level for these cytokines. IL-1alpha also increased mRNA transcript levels of protease-nexin-1, a secreted serine protease inhibitor expressed in the dermal papilla of anagen-stage hair follicles. Although DHT did not affect supernatant cytokine concentrations, the androgen altered mRNA transcript levels of several factors for DPC co-stimulated with IL-1alpha. In consideration of its in vitro activity profile, IL-1alpha may be an important modifier of dermal papilla activity as well as potentially influence androgen-regulated gene expression in DPC.

PMID:
16984260
[PubMed - indexed for MEDLINE]

Supplementing a Mediterranean diet with coenzyme Q10 lowers inflammation

01/30/2012

Note: There is your perfect diet waiting for you. If you feel this is it, then here is my support of your natural yearnings!

Friday, January 27, 2012. A crossover study described in the January, 2012 issue of the Journals of Gerontology Series A revealed that the addition of coenzyme Q10 (CoQ10) to a Mediterranean diet lowers a number of indicators of inflammation in older men and women.

Researchers at the University of Cordoba and the Instituto de Salud Carlos III in Spain enrolled ten men and ten women aged 65 and older who were not being treated for inflammation or elevated lipids. Participants were randomized to receive one of three dietary regimens for a four week period, followed by two additional four week periods in which the regimens previously not received were administered. The regimens consisted of a Mediterranean diet, which contains high amounts of vegetables, fruit, olive oil and other healthy foods; a Mediterranean diet supplemented with 200 milligrams per day coenzyme Q10, and a Western diet providing 38 percent of total energy as fat and containing high amounts of saturated fat. Fasting and postprandial blood samples collected at the end of each intervention were analyzed for the expression of genes involved in inflammation.

At the conclusion of the study, consumption of the Mediterranean diet was found to be associated with a reduction in the expression of a number of genes involved in the inflammatory process. The addition of coenzyme Q10 to the diet further reduced the expression of three significant genes, including interleukin 1-beta, in comparison with the other diets. In previous research involving the Mediterranean diet, the researchers observed a reduction in oxidative stress that occurs after a meal, which was further improved by CoQ10. "In healthy humans, plasma oxidative damage may be partially prevented by CoQ supplementation, which has been replicated in other populations, like psoriasis or coronary heart disease patients," Jose Lopez-Miranda and colleagues write.

They remark that the current study's results "support that the consumption of a Mediterranean diet supplemented with CoQ is beneficial for healthy aging of individuals. We can conclude that specific dietary intervention might be a new, interesting, and promising challenge in the treatment (and mainly prevention) of processes that lead to a rise in chronic inflammation and oxidative stress, such as cardiovascular, neurodegenerative diseases, and aging."

CausticSymmetry wrote:I wrote an article, it's a bit dated now, but will be re-published soon.

It refers to Interleukin-6. Here's a a snippet of it:

Omega-3 fatty acids, such as krill oil, can help suppress the inflammatory prostaglandin called interleukin 6 in response to DHT.

Abundant evidence exists suggesting that prostaglandins can affect the growth of human hair follicles. Prostaglandins are hormone-like molecules that affect inflammation and other necessary processes in the body. The hair follicle cells in balding scalps upregulate the prostaglandin interleukin 6 (IL-6). Interleukin 6 suppresses hair growth by affecting the growth stages (cell proliferation) of hair follicles. [1]

Interleukin 6 is signaled by balding dermal papilla cells, while silent in non-balding cells. Too much IL-6 shortens the growth stages (anagen) and prolongs the sleeping stages (catagen).

In a recent study, medical students were assigned either omega-3 fatty acid supplements or placebo. They were observed for a year to evaluate their stress levels.

It was found that those students who received omega 3 fatty acids had a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms when compared to the placebo group. [2]

[1]. J Invest Dermatol. 2011 Sep 1. doi: 10.1038/jid.2011.274
[2]. Brain Behav Immun. 2011 Jul 19.

Estrogen Increases Mitochondrial Efficiency and Reduces Oxidative Stress in Cerebral Blood Vessels

Chris Stirone,
Sue P. Duckles,
Diana N. Krause and
Vincent Procaccio

+ Author Affiliations

Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California (C.S., S.P.D., D.N.K.); Department of Pediatrics, College of Medicine, University of California, Irvine, Irvine, California (V.P.); Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, Irvine, California (V.P.)

Address correspondence to:
Dr. Vincent Procaccio, Center for Molecular and Mitochondrial Medicine and Genetics, University of California Irvine, Irvine, CA 92697. E-mail: vproca@uci.edu

Abstract

We report here that estrogen (E2) modulates mitochondrial function in the vasculature. Mitochondrial dysfunction is implicated in the etiology of vascular disease; thus, vasoprotection by estrogen may involve hormonal effects on the mitochondria. To test this hypothesis, mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with or without E2 replacement. Estrogen receptor-α (ER-α) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E2 treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-α, cytochrome c, subunit IV of complex IV, and manganese superoxide dismutase, all encoded in the nuclear genome, and subunit I of complex IV, encoded in the mitochondrial genome. Levels of glutathione peroxidase-1 and catalase, however, were not affected. Functional assays of mitochondrial citrate synthase and complex IV, key rate-limiting steps in energy production, showed that E2 treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E2-treated animals. In vitro incubation of cerebral vessels with 10 nM 17β-estradiol for 18 h also elevated levels of mitochondrial cytochrome c. This effect was blocked by the estrogen receptor antagonist fulvestrant (ICI-182,780, Faslodex) but was unaffected by inhibitors of nitric-oxide synthase or phosphoinositide-3-kinase. Nuclear respiratory factor-1 protein, a primary regulator of nuclear gene-encoded mitochondrial genes, was significantly increased by long-term estrogen treatment in vivo. In summary, these novel findings suggest that vascular protection by E2 is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.

Received May 10, 2005.

CausticSymmetry wrote:I wrote an article, it's a bit dated now, but will be re-published soon.

It refers to Interleukin-6. Here's a a snippet of it:

Omega-3 fatty acids, such as krill oil, can help suppress the inflammatory prostaglandin called interleukin 6 in response to DHT.

Abundant evidence exists suggesting that prostaglandins can affect the growth of human hair follicles. Prostaglandins are hormone-like molecules that affect inflammation and other necessary processes in the body. The hair follicle cells in balding scalps upregulate the prostaglandin interleukin 6 (IL-6). Interleukin 6 suppresses hair growth by affecting the growth stages (cell proliferation) of hair follicles. [1]

Interleukin 6 is signaled by balding dermal papilla cells, while silent in non-balding cells. Too much IL-6 shortens the growth stages (anagen) and prolongs the sleeping stages (catagen).

In a recent study, medical students were assigned either omega-3 fatty acid supplements or placebo. They were observed for a year to evaluate their stress levels.

It was found that those students who received omega 3 fatty acids had a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms when compared to the placebo group. [2]

[1]. J Invest Dermatol. 2011 Sep 1. doi: 10.1038/jid.2011.274
[2]. Brain Behav Immun. 2011 Jul 19.

How Estrogen Could Help Protect Women from Cardiovascular Disease

ScienceDaily (Aug. 11, 2011) — The sex hormone estrogen could help protect women from cardiovascular disease by keeping the body's immune system in check, new research from Queen Mary, University of London has revealed.
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The study has shown that the female sex hormone works on white blood cells to stop them from sticking to the insides of blood vessels, a process which can lead to dangerous blockages.

The results could help explain why cardiovascular disease rates tend to be higher in men and why they soar in women after the menopause.

The researchers compared white blood cells from men and pre-menopausal women blood donors. They found that cells from premenopausal women have much higher levels of protein called annexin-A1 on the surface of their white blood cells.

The scientists also found that annexin-A1 and estrogen levels were strongly linked throughout the menstrual cycle.

White blood cells play a vital role in protecting the body from infections. When they are activated they stick to the walls of blood vessels. This process normally helps the cells to tackle infection but if it happens too much, it can lead to blood vessel damage, which in turn can lead to cardiovascular disease. However, when annexin-A1 is on the surface of these white blood cells, it prevents them from sticking to the blood vessel wall.

The new research shows that estrogen can move annexin-A1 from inside the white blood cell, where it is normally stored, to the surface of the cells, thereby preventing the cells from sticking to blood vessel walls and causing vascular damage. This may have important implications in cardiovascular disease.

Dr Suchita Nadkarni from the William Harvey Research Institute, Queen Mary, University of London, who led the research, said: "We've known for a long time that estrogen protects pre-menopausal women from heart disease, but we don't know exactly why. This study brings us a step closer to understanding how natural estrogen might help protect our blood vessels.

"We've shown a clear relationship between estrogen levels and the behaviour of these white blood cells. Our results suggest that estrogen helps maintain the delicate balance between fighting infections, and protecting arteries from damage that can lead to cardiovascular disease.

"Understanding how the body fights heart disease naturally is vital for developing new treatments."

The study was co-funded by the British Heart Foundation, the Wellcome Trust and the National Institutes of Health Research (NIHR).