Estrogens Augment Cell Surface TLR4 Expression on Murine Macrophages and Regulate Sepsis Susceptibility in Vivo
ABSTRACT 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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- "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 "
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 · 1.96 Impact Factor
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- "In addition LBP protein levels are not changed in AERKO animals in response to either E2 or the ERα selective agonist. It is likely treatment with an ERα selective agonist may result in hypersensitization to microbial infection which can be both harmful in supporting a robust susceptibility to infection by certain bacteria or viruses, however it has also been shown to be beneficial in providing strong protection against other types of bacterial infection (Rettew et al., 2009). LBP levels in BERKO animals are altered in response to the ERα selective agonist but do not have significant responses to E2. "
ABSTRACT: Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ) are steroid nuclear receptors that transduce estrogen signaling to control diverse physiological processes linked to reproduction, bone remodeling, behavior, immune response and endocrine-related diseases. In order to differentiate between ERα and ERβ mediated effects in vivo, ER subtype selective biomarkers are essential. We utilized ERα knockout (AERKO) and ERβ knockout (BERKO) mouse liver RNA and genome wide profiling to identify novel ERα selective serum biomarker candidates. Results from the gene array experiments were validated using real-time RT-PCR and subsequent ELISA's to demonstrate changes in serum proteins. Here we present data that Lipopolysacharide Binding Protein (LBP) is a novel liver-derived ERα selective biomarker that can be measured in serum.Biomarkers 03/2012; 17(2):172-9. DOI:10.3109/1354750X.2012.654406 · 2.52 Impact Factor
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- "However, the inhibition of function is hormone receptor dependent, as demonstrated through the use of hormone receptor positive and negative cell lines as well as hormone receptor antagonists (Lesmeister et al., 2005). In contrast to the above, E 2 has been shown to promote the expression of TLR4 (Rettew et al., 2009) as well as inflammatory mediators through activation of TLR4 by LPS through estrogen receptor alpha signaling. This effect was demonstrated by an experiment alleviating the negative regulation of TLR4 signaling pathway (Calippe et al., 2010). "
ABSTRACT: Toll-like receptors (TLRs) are evolutionarily conserved innate immune receptors that recognize pathogen specific molecular pattern (PAMPs) in an efficient, non-self-reactive manner and initiate specific immune signaling that culminates in triggering antigen-specific adaptive responses. Different TLR genes in domestic animal species have been characterized and accumulating evidence from recent studies indicates an extended role for TLR signaling in reproductive physiology. In females, TLRs have been implicated in the regulation of ovulation, fertilization, gestation and parturition, as well as in pathological conditions such as endometritis and mastitis. In males, TLRs play a role in steroidogenesis and spermatogenesis. Use of TLR agonists has also been shown to be effective in the treatment of certain reproductive tract infections. Moreover, gene polymorphisms in TLRs have been associated with mastitis providing evidence that TLRs can potentially be exploited as markers in future breeding programs. The aim of this review is to provide a comprehensive treatise on role of TLRs in male and female reproductive physiology and associated pathology in domestic livestock.Animal reproduction science 05/2011; 125(1-4):1-12. DOI:10.1016/j.anireprosci.2011.03.008 · 1.58 Impact Factor