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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Available from: Yvette Huet, Nov 25, 2015
    • "lipopoylsaccahirde binding protein for promoting resistance to bacterial infections (Rettew et al., 2009). Similarly, stress related proteins like heat shock proteins (HSPs) were increased in cervico-vaginal fluid during oestrus in buffaloes (Muthukumar et al., 2014a) and in the brain vasculature of rats by oestradiol treatment to combat the stress conditions. "
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    ABSTRACT: Salivary RNA-based biomarkers are not available for any physiological condition in farm animals. Hence, an objective of this study was to perform salivary transcript analysis in buffaloes. Saliva, after removal of the cells and particulate matter, was directly used for RT-PCR without RNA isolation. Direct saliva transcript analysis (DSTA) showed a suggestively significant higher expression of the Heat shock protein 70 (HSP70) and Toll-like receptor 4 (TLR4) at oestrus than the diestrous period in buffaloes by a non-parametric Mann-Whitney U test. Therefore, DSTA without RNA isolation is an easy method to identify salivary RNA markers for oestrus detection in buffaloes.
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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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    • "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.
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