Estrogens Augment Cell Surface TLR4 Expression on Murine Macrophages and Regulate Sepsis Susceptibility in Vivo

Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA.
Endocrinology (Impact Factor: 4.5). 05/2009; 150(8):3877-84. DOI: 10.1210/en.2009-0098
Source: PubMed


Gender-based differences exist in infectious disease susceptibility. In general, females generate more robust and potentially protective humoral and cell-mediated immune responses after antigenic challenge than their male counterparts. Furthermore, evidence is accumulating that sex may also influence the early perception of microbial challenges and the generation of inflammatory immune responses such as sepsis. These differences have previously been attributed to the actions of reproductive hormones. Whereas androgens have been shown to suppress acute host immune responses to bacterial endotoxin challenge, estrogens have been found to promote increased resistance to bacterial infections. However, the mechanisms by which estrogens exert immunoprotective effects have not been established. In this study, we investigated the in vivo effects of 17beta-estradiol on endotoxin susceptibility in mice. Importantly, we have examined the actions of this female reproductive hormone on the expression of pattern recognition receptors that recognize bacterial endotoxin by key innate immune sentinel cells. We show that removal of endogenous estrogens decreases both pro- and antiinflammatory cytokine production, with a concomitant reduction in circulating levels of lipopolysaccharide-binding protein and cell surface expression of Toll-like receptor 4 on murine macrophages. Exogenous in vivo replacement of 17beta-estradiol, but not progesterone, significantly elevates sera lipopolysaccharide-binding protein levels and cell surface expression of Toll-like receptor 4 and CD14 on macrophages. Furthermore, this effect corresponds with significantly higher inflammatory cytokine levels after in vivo lipopolysaccharide challenge and a marked increase in endotoxin-associated morbidity. Taken together, these data provide a potential mechanism underlying the immunoenhancing effects of estrogens.

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    • "Thus, our findings may not be representative for naturally cycling or post-menopausal women. Given that inflammatory and sickness responses in animals have been shown to be influenced by the estrous cycle (Avitsur et al., 1995; Engeland et al., 2006), and given the putative role of estrogens in driving the more pronounced pro-inflammatory response in women (Rettew et al., 2009), it would be particularly interesting to include also women in the follicular and luteal phases of the menstrual cycle in future studies. Finally, in order to induce moderate immune activation commonly occurring under normal life conditions, we used a comparatively low dose of endotoxin, leaving the possibility open that sex differences in mood and anxiety become only apparent under more severe inflammatory conditions. "
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    ABSTRACT: Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.013 · 5.89 Impact Factor
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    • "It had been advanced that this dampened brain inflammatory response in females is brought about by the anti-inflammatory role of female sex hormones (namely 17β-estradiol [E] and progesterone [Pr]; Stein and Hoffman, 2003; Amantea et al., 2005). However, the potential beneficial role of ovarian hormones remains highly debated and controversial as these hormones have been shown to either promote (Calippe et al., 2008, 2010; Rettew et al., 2009; Seillet et al., 2012) or suppress brain inflammatory responses (Pozzi et al., 2006; Vegeto et al., 2008). "
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    ABSTRACT: Experimental and epidemiological data show that the severity and the duration of brain inflammation are attenuated in females compared to males. This attenuated brain inflammation is ascribed to 17β-estradiol. However, several studies suggest that 17β-estradiol is also endowed with proinflammatory properties. The aim of the present study is to assess the effect of hormonal replacement therapies on LPS-induced brain inflammation and its consequent effect on newly born neurons. Bilaterally ovariectomized rats received intrastriatal injection of lipopolysaccharide (LPS, 250 ng/µl) and subsequently were given daily subcutaneous injections of either vehicle, 17β-estradiol (25 µg/kg) or 17β-estradiol and progesterone (5mg/kg). Microglial activation and newly-born neurons in the rostral migratory stream were monitored using double immunofluorescence. Nuclear factor κB (NFκB) signaling pathway and its target inflammatory proteins were assessed by either western blot (cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6)) or ELISA (Tumor Necrosis Factor-α (TNFα)). LPS induced activation of microglia, promoted NFκB signaling pathway and enhanced production of the pro-inflammatory proteins (TNFα and COX-2). These proinflammatory responses were not attenuated by 17β-estradiol-injection. Supplementation of 17β-estradiol with progesterone significantly dampened these pro-inflammatory processes. Interestingly, LPS-induced brain inflammation dampened the number of newly born neuron in the rostral migratory stream. Administration of combined 17β-estradiol and progesterone resulted in a significantly higher number of newly born neurons when compared to those seen in rats given either vehicle or 17β-estradiol alone. These data strongly suggest that combined 17β-estradiol and progesterone, and not 17β-estradiol alone, rescues neurogenesis from the deleterious effect of brain inflammation likely via the inhibition of the signaling pathways leading to the pro-inflammatory gene activation.
    Frontiers in Cellular Neuroscience 05/2014; 8:146. DOI:10.3389/fncel.2014.00146 · 4.29 Impact Factor
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    • "Dose dependent decrease in ConA-stimulated thymocyte proliferation Hareramadas and Rai (2006) E2 Homo sapiens Increased expression of neuronal nitric oxide synthase in neutrophils Molero et al. (2002) E2 H. sapiens In vitro monocyte/macrophage cell line exhibited increased expression of NF-jB, subsequent increased NF-jB DNA binding, and decreased apoptosis Cutolo et al. (2005) E2 Mus musculus Increased transcription of TLR2, TNF-a, IL-12 after LPS injection Soucy et al. (2005) E2 M. musculus Increased TLR4 and CD14 expression in macrophages Rettew et al. (2009) E2 Mya arenaria Inhibition of hemocyte phagocytosis at concentrations of 10 and 20 nmol E2 "
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    ABSTRACT: Endocrine-disrupting chemicals (EDCs) alter cellular and organ system homeostasis by interfering with the body's normal physiologic processes. Numerous studies have identified environmental estrogens as modulators of EDC-related processes in crocodilians, notably in sex determination. Other broader studies have shown that environmental estrogens dysregulate normal immune function in mammals, birds, turtles, lizards, fish, and invertebrates; however, the effects of such estrogenic exposures on alligator immune function have not been elucidated. Alligators occupy a top trophic status, which may give them untapped utility as indicators of environmental quality. Environmental estrogens are also prevalent in the waters they occupy. Understanding the effects of these EDCs on alligator immunity is critical for managing and assessing changes in their health and is thus the focus of this review.
    Archives of Environmental Contamination and Toxicology 11/2013; 65(4):704-714. DOI:10.1007/s00244-013-9953-x · 1.90 Impact Factor
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