Article:Immunomodulatory Effects of 17-Estradiol on Epithelial Cells during Bacterial Infections (6136541)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at Its title is Immunomodulatory Effects of 17-Estradiol on Epithelial Cells during Bacterial Infections and the publication date was 2018-08-29. The initial author is Ivan Medina-Estrada.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.

Converted JATS paper:

Journal Information

Title: Journal of Immunology Research

Immunomodulatory Effects of 17β-Estradiol on Epithelial Cells during Bacterial Infections

  • Ivan Medina-Estrada
  • Nayeli Alva-Murillo
  • Joel E. López-Meza
  • Alejandra Ochoa-Zarzosa

1Trayectoria en Genómica Alimentaria, Universidad de la Ciénega del Estado de Michoacán de Ocampo, Sahuayo De Morelos, MICH, Mexico

2Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, GTO, Mexico

3Centro Multidisciplinario de Estudios en Biotecnología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, MICH, Mexico

Publication date (collection): /2018

Publication date (epub): 8/2018


The innate immune system can function under hormonal control. 17β-Estradiol (E2) is an important sexual hormone for the reproductive cycle of mammals, and it has immunomodulatory effects on epithelial cells, which are the first line of defense against incoming bacteria. E2 regulates various pathophysiological processes, including the response to infection in epithelial cells, and its effects involve the regulation of innate immune signaling pathways, which are mediated through estrogen receptors (ERs). E2 modulates the expression of inflammatory and antimicrobial elements such as cytokines and antimicrobial peptides. The E2 effects on epithelial cells during bacterial infections are characterized by an increase in the production of antimicrobial peptides and by the diminution of the inflammatory response to abrogate proinflammatory cytokine induction by bacteria. Here, we review several novel molecular mechanisms through which E2 regulates the innate immune response of epithelial cells against bacterial infections.


1. Introduction

17β-Estradiol, also known as E2 (due to its two hydroxyl groups), is a steroidal hormone derived from cholesterol and is the most predominant and potent sexual hormone during the reproductive stage of females [[1]]. The principal effects of E2 are associated with reproductive and sexual functions, although it is also involved in the development of different pathologies, such as cancer, autoimmune diseases, and infectious processes, where the innate immune response (IIR) can be altered by this hormone [[2]].

The main immunomodulatory effects of E2 have been described in the epithelium of the reproductive tract of females, where it modulates the IIR helping to maintain the microbiota in addition to favoring an anti-inflammatory environment [[3][5]]. E2 can also regulate the differentiation and proliferation of epithelial cells in several tissues (e.g., epithelial mammary cells) [[6], [7]]. The anti-inflammatory properties of E2 have been demonstrated in different epithelial models, such as the human uterus, rat oviduct, and mouse intestine, and it is well known that E2 can reverse the inflammatory response induced by bacterial components or whole pathogens. In addition, in some models, it has been reported that E2 improves the antimicrobial response against different pathogens inducing the production of antimicrobial peptides. To date, there is little information concerning the immunomodulatory effects of E2 in epithelial cells during infections [[3], [8], [9]]. Thus, the objective of this review was to provide the current knowledge on the pathways and elements that participate in the immunomodulatory effects of E2 in epithelial cells during bacterial infections.

2. General Aspects of E2

E2 is the most abundant and potent natural estrogen in all vertebrates. E2 is a C18 steroid derived from cholesterol and is the main estrogen present in the serum of mammal females at reproductive age. In humans and other vertebrates, estrogens are made primarily in the female ovaries, but small amounts of this hormone may be produced in the male testes as well as in the adrenal glands, brain, and fat tissue of both sexes. E2 synthesis involves several chemical intermediates, such as progestagens and androgens (e.g., testosterone), which are derived from cholesterol (Figure 1). Testosterone undergoes conversion to estradiol by aromatase (P450aro = CYP19), resulting in the loss of one carbon (C19) and the aromatization of the A-ring, thereby producing E2. An alternative pathway to synthesize E2 occurs through the conversion of androstenedione to estrone (via aromatase), which can be enzymatically converted to E2 [[10]].

The main targets of E2 are the reproductive female organs (ovary, uterus, and mammary gland). E2 acts in a vast variety of cell populations; however, its main targets are epithelial cells. This hormone regulates epithelial cell differentiation, proliferation, and apoptosis, which are processes intimately linked to the female reproductive cycle such as lactation or ovulation [[11][13]]. E2 functions are diverse and play important roles in the regulation of metabolism (body fat distribution), hemodynamics (vascular tone), reproduction (ovulation and development of primary and secondary sexual characters, including growth and involution of the mammary gland), and pathological processes, such as cancer and diseases, where the immune response is compromised [[11], [14], [15]].

2.1. Estrogen Receptors

The effects of E2 are mediated by estrogen receptors (ERs), which are classified as ERα (565 aa) and ERβ (530 aa), and these receptors were characterized in 1973 for the first time in a rat uterus [[16]]. ERs belong to the superfamily of nuclear receptors, functioning as transcriptional factors or associating with other transcriptional factors to regulate the expression of many genes related to the functions described for E2 [[17]]. In addition to nuclear receptors, there is a third ER, namely GPR30, which belongs to the G protein-coupled receptor family. The GPR30 receptor is located in the endoplasmic reticulum and plasma membrane and is mainly associated with nongenomic responses [[16], [18]].

The nuclear receptors ERα and ERβ have well defined the functional and structural subunits. Both ERs remain inactive when they are bound to the heat shock protein complexes Hsp70 and Hsp90; however, binding with their ligands (e.g., E2) induces a conformational change, which favors the dissociation of the ER complex and promotes ER activation and translocation to the nucleus. In the nucleus, ER interacts with estrogen response elements (EREs) present in the DNA sequence (the minimum consensus sequence is a palindromic repeat sequence of 5′-GGTCAnnTGACC-3′). EREs are present in many gene promoters such as oxytocin, c-fos, c-myc, TGF-α, prolactin, complement proteins, and lactoferrin [[19]]. ERs can also be activated independent of estrogen binding (nonclassical signaling). This kind of ER activation is the consequence of several posttranslational modifications (phosphorylation, acetylation, and methylation) induced by different enzymes [[20]].

E2 levels vary depending on the species and its reproductive stage. The range in mammal females oscillates between 50 pg/ml (standard for basal condition) and 1500 pg/ml (standard for the preovulatory phase), which is associated with the effects that E2 have on reproduction and is the reason why sexual hormone levels are varied in mammals [[21], [22]]. ERs as well as E2 have been associated with some pathologies, such as cancer, being breast cancer the principal disease in which ERs are involved [[23], [24]]. Nevertheless, ERs and E2 also play an important role in the IIR to different stimuli. For example, females are more susceptible to develop inflammatory lung conditions and sex hormones have been implicated in this process [[25]]. However, the immune mechanisms responsible for sex-based disparity are unknown. The data suggest that specific sex hormone influences the IIR [[1]]. Accordingly, ERs can modulate the activation of transcriptional factors associated with the IIR, such as NF-κB, SP1, AP-1, and C/EBPβ. As a consequence, ERs regulate the transcription of elements of the inflammatory response, such as proinflammatory cytokines, anti-inflammatory cytokines, antimicrobial peptides, and chemokines. In addition, in response to their ligands, ERs regulate different signaling pathways, which can also be associated with the IIR [[26]].

GPR30 is associated with cellular estrogen functions, including canonical genomic signaling and novel nongenomic responses. The nongenomic events include production of second messengers (Ca2+ and cAMP), activation of tyrosine kinase receptors (such as EGFR and IGF-IR), and activation of different protein/lipid kinase pathways (PI3K, Art, MAPK, Scr, and PKA/PKC) [[16]]. Thus, GPR30 signaling pathways are also related to the regulation of the IIR. However, the information concerning these functions is scarce.

3. Hormonal Regulation of the Innate Immune Response

Diverse hormones have been reported to participate in the modulation of the IIR, which is activated by different stimuli such as those occurring in infectious diseases or stress conditions, which can modulate the inflammatory response. This response during infections is mainly characterized by the production of proinflammatory cytokines, namely tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), and interleukin-6 (IL-6), as well as chemokines. These molecules are secreted by the injured tissue as well as by innate cells such as macrophages, dendritic cells, and mast cells in order to recruit neutrophils and monocytes to the affected tissue. Through the release of antimicrobial molecules and active phagocytosis, innate immune cells act to eliminate the foreign agent and recover tissue homeostasis [[27]]. Sexual hormones play an important role during the IIR to infection in particular estradiol, progesterone, and androgens [[28]].

On the other hand, the stress response stimulates the hypothalamic-pituitary-adrenal (HPA) axis, inducing the release of the corticotrophin-releasing hormone (CRH) from the hypothalamus to the pituitary portal system. Corticotrophin is then released from the pituitary gland to the systemic circulation, stimulating the suprarenal cortex to reliberate glucocorticoids [[29]]. At the same time, stress induces the activation of the sympathetic nervous system, which leads to catecholamine release from the autonomic nervous terminals and the adrenal medulla [[30]]. Glucocorticoids and catecholamines have well-known immunoregulatory functions, namely, reducing the inflammatory response activated by the infection, which leads to the production of anti-inflammatory cytokines [[29]].

In addition to the HPA axis, other hormones have been implicated in the regulation of the IIR. Indeed, receptors for many hormones are expressed in cells from the innate and adaptive immune systems, which is the case for prolactin, growth hormone, thyroid hormone, or estrogen. The immunomodulatory effects of the hormones depend on the type of tissue, the hormone concentration, the physiological context, or the activated signaling pathway [[31]].

With regard to estradiol, its immunomodulatory properties comprise both the development as well as the function of innate immune cells. In this sense, ERs are expressed in immune cells triggering different signaling pathways. Estradiol exhibits both proinflammatory and anti-inflammatory responses related to hormone concentrations [[26]].

The transition to menopause, characterized by declining estradiol levels, has an impact on immunosenescence increasing the susceptibility to infection diseases and decreasing the efficacy of vaccination. These effects in postmenopausal women are characterized by an upregulation in the production of the cytokines TNF-α, IL-1β, IL-10, and IL-6, the stimulation of the cytotoxic activity of NK cells, and a diminished phagocytic capacity of dendritic cells (DCs), which leads to impaired antigen presentation and activation of the adaptive immune system. Upon hormone replacement therapy, these age-related changes can be partially reverted [[32]]. In addition, women are susceptible to develop postmenopausal pathologies, such as diabetes, atherosclerosis, and cardiovascular diseases, all of them characterized by inflammatory hallmarks. Epidemiological studies worldwide suggest that hormonal therapy, which mainly consists of E2 administration (through different routes and hormonal combinations), can revert or ameliorate these inflammatory conditions. However, there are contradictory results and further research is necessary in order to clarify the effects of hormone replacement therapy in the development of inflammatory diseases [[33]].

3.1. Roles of Epithelial Cells during the Innate Immune Response

Mucosal epithelial cells display an autonomous IIR against invading bacteria and are able to discriminate between pathogen and nonpathogen microorganisms, thereby generating an inflammatory response against pathogens. This discrimination can be achieved through different mechanisms. For example, mucosal epithelial cells are covered by a film of thick mucus layer that protects epithelium from unwanted microorganisms. The mucus layer serves as matrix in which antimicrobial peptides produced by the epithelial lining are embedded [[34]]. However, many bacterial species invade epithelial cells to escape from antimicrobial substances or the immune system and they are able to adhere and invade epithelia [[35]].

Bacteria express molecules that can be recognized by the innate immune system, and these elements are known as pathogen-associated molecular patterns (PAMPs) [[36]]. PAMPs are recognized by transmembrane and cytoplasmic receptors that are expressed by a broad range of cell types, including epithelial cells. These receptors are known as pathogen-recognizing receptors (PRRs), such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs), or coreceptors, such as CD14 and CD16 [[37]]. Even though being a “classic” defense, cells such as macrophages, neutrophils, and dendritic cells have a great quantity and different types of these receptors. Epithelial cells also express these receptors and are effective against infections. The ligands for these types of receptors are varied and include fungal or bacterial membrane constituent molecules or viral or bacterial genetic material [[35]]. There is evidence supporting that PAMPs from symbiotic microorganisms are less agonistic to PRRs than those of pathogenic microorganisms inducing immune tolerance or physiological inflammation, which maintains a significant proportion of resident macrophages and dendritic cells in a situation of immaturity, and of a proper balance between regulatory T cell (Treg) lymphocytes and inflammatory lymphocytes (Th1 and Th17 T) [[34]].

The recognition of PAMPs from pathogens triggers signaling pathways and, as a consequence, activates different transcriptional factors, which regulate cytokine, chemokine, or antimicrobial peptide gene expression and protein secretion; all of these elements are associated with the IIR. The objective of this response is to eliminate the pathogen and repair the damage that it caused (Figure 2). The most commonly activated elements after the recognition of pathogens are as follows: members of MAPKs, transcriptional factors, including NF-κB, AP-1, and SP1; proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6; anti-inflammatory cytokines, including IL-10; antimicrobial peptides; and oxygen- and nitrogen-reactive species [[38]]. In Figure 2, a general overview of the signaling inflammatory events of epithelial cells during bacterial infections is shown.

4. Functions of E2 in Epithelial Cells

In general, the effects of E2 on epithelial cells activate the classic genomic pathway, which occurs over the course of hours. E2 binding to ER induces some conformational changes allowing ER to dissociate from chaperone heat-shock proteins and dimerize with other receptors (ERs). This complex binds directly either to an ERE in target gene promoters or to transcriptional factors via protein tethered to DNA [[11]]. In contrast, nongenomic signaling via E2-ERs occurs quickly (minutes or seconds). The ligand-receptor complex can also interact with G proteins, growth factor receptors, or tyrosine kinases, thus facilitating the interaction and rapid intracellular signaling [[16]].

Both classic and nongenomic E2-ER signaling pathways lead to a wide variety of biological cell functions in different epithelia. The classic effects of E2 on epithelial cells are associated with proliferation, differentiation, and cellular apoptosis. For example, the epithelial cells of mammary glands—one of the E2 target tissues—are exposed to major morphological and biochemical changes during the lactation cycle [[12]]. Additionally, steroid hormones of the ovary and placenta have been implicated as stimulators of mammary gland development, involving complex interactions between E2 and epithelial mammary cells, resulting in mammogenesis, lactogenesis, galactopoiesis, and involution [[39]]. The genomic biological responses of E2 in mammary glands are predominantly mediated by ERα, which is localized in epithelial compartments. Mammary proliferation depends on the nature of the reproduction cycle. In many species, duct extension and branching are followed by growth of alveoli lobules. During milk production, basal levels of E2 are necessary to maintain metabolism and several specific hormone actions and they are also expected to play a permissive role during lactation. After lactation, the mammary gland has a gradual involution. The induction of apoptosis mediated by E2 (1 × 10−7 mol/ml) is necessary for this process, which requires ERα at 2–4 weeks of involution and ERβ at 2–4 weeks after this event [[13]]. For all of the E2 effects described, different factors associated with E2-ER signaling pathways are involved, such as epidermal growth factor (EGF), TGF-α, insulin-like growth factor (ILG-F), and TNF-α. These elements modulate the survival and apoptosis of mammary epithelial cells at 10−10 mol/ml E2 [[40]].

The female reproductive tract (epithelial cell specificity) is exposed to E2 effects, which influence processes associated with reproduction and immunity [[4]]. The vagina, cervix, uterus, oviduct, and ovaries are strongly influenced by E2. This hormone increases the proliferation of epithelial cells in both the uterus and the vagina. For example, it has been observed in mouse uterus that after the preovulatory E2 surge, early (within 6 h) morphological and biochemical changes occur including vascular permeability, hyperemia, prostaglandin release, glucose metabolism, eosinophil infiltration, and lipid and protein synthesis [[41]]. In addition, E2 induces ERα recruitment to ERE sites in target genes of mouse uterus, which leads to RNA and DNA syntheses, epithelial cell proliferation, and their differentiation toward a columnar secretory epithelium [[42]]. These effects are achieved at long time periods (after 24–72 h).

Otherwise, vaginal epithelial cells respond to E2 by undergoing cornification (production of keratins and involucrin), a process that involves both proliferation and differentiation. These effects are mediated by ERα in a direct way as well as through a paracrine route (involving stroma cells) [[43]].

E2 also modulates the permeability of the lower female reproductive tract (vagina and ectocervix). Epithelial cells are linked by tight junction proteins, regulating the traffic of molecules across the epithelium. In the lower female reproductive tract, the stratified squamous epithelium shows tight junctions between basal epithelial cells. E2 increases the relaxation of epithelial tight junctions, which induces the flux across the epithelium. These effects are mediated by the expression of claudin and occludin [[9], [44]].

E2 also promotes lactobacillus growth in vaginal epithelial cells by increasing the storage of glycogen in the suprabasal and apical layers [[45]]. Glycogen is a substrate for acid production by these bacteria maintaining a low-pH environment [[7]]. Epithelial cells from the urinary tract (bladder epithelium) are also influenced by E2, and these cells play an important role of protection from infectious diseases where E2 has a relevant function, increasing the production of antimicrobial peptides and tightening intercellular connection, thereby preventing bacteria to reach the cells where they can hide and cause infection [[7]]. In vitro and in vivo studies indicate that the production of different antimicrobial peptides increases in bladder epithelial cells after E2 treatment (see below).

In addition, it has been shown in rabbit bladders that E2 increases the volume of smooth muscle cells as well as vascularization, promoting bladder contraction [[46]]. In the absence of E2, the residual urine increases, whereas the urine flow is reduced, impairing the mechanical clearance of bacteria [[47]].

4.1. Immunomodulatory Effects of E2 in Epithelial Cells

The epithelial IIR is fast and acts directly upon the pathogen attack or tissue damage [[48]]. Several studies have demonstrated the regulation of the IIR of epithelia by E2. In all of the epithelial models where E2 plays an immunomodulatory role, E2 has also been demonstrated to have anti-inflammatory effects. In human epithelial cells from the endometrium, E2 (10−7 M) shows an anti-inflammatory action reversing the effects caused by PAMPs, such as Poly I:C [[49]]. In addition, E2 can block the inflammatory effects caused by IL-1β and lipopolysaccharide (LPS) from Escherichia coli in human and rat uterus [[6], [49]]. In bovine oviduct, LPS stimulation increases the secretion of IL-1β and TNF-α and it induces the expression of TLR2 and TLR4. However, E2 (1 ng/ml) reverses these inflammatory effects [[44]]. In the same way, the production of nitric oxide induced via mechanical damage or LPS stimulation in rat intestinal epithelium is diminished by E2 [[3], [50]].

Despite the aforementioned evidence, the relation of E2 with the IIR during infectious processes has not been properly analyzed because epithelial cells are challenged with PAMPs or proinflammatory cytokines instead of whole bacteria, in most of the models.

Experimental evidence suggests that E2 performs its immunomodulatory effects through the regulation of TLRs because they are the main PRRs that trigger the IIR signaling pathways. E2 (10−8 M) through ERα modulates the signaling of TLR3 (which recognizes double-stranded RNA) in the human reproductive tract during the beginning of the gestational cycle. Interestingly, the increase of E2 reduces the abundance of TLR3 favoring an anti-inflammatory environment [[51]].

E2 also regulates different inflammatory transcriptional factors. For example, in rat aortic smooth muscle cells, E2 inhibits the activation of NF-κB, thus avoiding its dissociation from the IκB inhibitor [[52]]. In addition, it is known that in both human uterine and urinary epithelial cells, E2 can modulate the activation of other transcriptional factors such as AP-1, SP1, STAT, and vitamin D receptor (VDR), which also participate in the regulation of the IIR. In this sense, E2 inhibits STAT phosphorylation and promotes the activation of VDR, modulating the MAPK signaling pathway (Figure 3) [[6], [7], [53]]. Finally, in human endometrium, E2 (10−8 M or 10−9 M) inhibits the protein levels of the IL-1β receptor, thus reversing the stimulatory effects of IL-1β on mRNA expression of TNF-α, IL-8, and NF-κB [[6]]. A summary of the effects of E2 on the IIR of epithelial cells is shown in Figure 3.

4.2. Antimicrobial Activity of E2 against Bacterial Infections in Epithelial Cells

Antimicrobial peptides (AMPs) are a diverse group of molecules with a broad range of activities, including cytotoxic, antifungal, antibacterial, or immunomodulatory effects. In mammals, these molecules are produced by different types of cells, highlighting those that are in intimate contact with pathogens such as epithelial cells [[54]]. In different models of infection, E2 exerts antibacterial activity against many pathogens because it favors the expression and secretion of AMPs. Human beta defensin-2 (HBD-2) is one of the most relevant AMPs in the human reproductive tract, and its secretion is regulated by E2. For example, human uterine epithelium exposed to LPS in the presence of E2 (10−3 M) shows increased secretion of the AMPs, calcineurin-like metallophosphoesterase superfamily protein (SLP1), and HBD-2, as well as decreased production of proinflammatory cytokines via NF-κB inhibition [[3]]. Moreover, in vaginal epithelium, E2 (2 nM) induces HBD-2 secretion in response to LPS [[55]]. In addition, growth inhibition of S. aureus in the presence of E2 has been reported in a rat uterus and this inhibition is attributed to AMP secretion in the uterine lumen [[8]]. In the urinary tracts of women treated with E2 (10−3 M), a lesser recurrence of Escherichia coli infections has been observed, which is associated with the production of AMPs, such as defensins (HBD-1 and HBD-2), and the homeostasis of the common microbial flora [[3]]. In similar models (postmenopausal women treated with estrogens), a diminished risk of bacterial infections has been observed due to the increase of mRNA coding for the AMPs HBD-1 and HBD-3, as well as psoriasin and cAMP [[3], [6], [8]].

During the menstrual cycle, the fluctuation of hormonal concentrations leads to immune changes in the female reproductive tract (FRT). These changes vary depending on the location (upper or lower FRT) and the hormonal concentrations, which fluctuate differentially across the tissues in relation to their levels in circulation. At mid-cycle when E2 levels are high, there is a window of vulnerability for the establishment of infections in the lower FRT (viral, bacterial, or fungal) as a result of the inhibition in the production of AMPs (such as HBD-2). By contrast, in the upper FRT (uterus) persists a reduced activity of cytotoxic cell at a time when the production of AMPs is enhanced optimizing the conditions for a successful implantation [[9]]. In addition, during the proliferative stage of the menstrual cycle, cervical/vaginal secretion contains higher levels of other AMPs in relation with other stages of the cycle (medium and secretory phases), for example, the secretory leukocyte protease inhibitor-1 (SLP1), HBD-1, human neutrophil proteins 1–3 (HNP1–3), or lactoferrin [[5], [6], [56], [57]].

In animal models, immunomodulatory effects of E2 also comprise the production of AMPs. For example, SBD-1 (sheep beta-defensin-1) defensin is induced in ovine oviduct epithelial cells by E2 (10−8 M) [[5]]. In male rabbits exposed to S. aureus (a strain causing toxic shock), E2 treatment protects against the infection [[58]]. Similarly, in rat uterus using in vivo and in vitro experiments, higher levels of E2 induce resistance against E. coli infection and this effect is attributed to the secretion of antimicrobial molecules [[8]]. In human bladder epithelial cells, E2 induces the production of defensins HBD1-3, ribonuclease (RNase) 7, psoriasin, and cathelicidin; these effects can be associated with a reduced E. coli infection [[59]]. These findings indicate that AMP production constitutes a relevant defense mechanism induced by E2 in epithelia.

Evidence from our group indicates that bovine mammary epithelial cells (bMECs) treated with E2 produce antimicrobial molecules (probably AMPs) as the conditioned medium of bMECs treated with E2 inhibits the viability and growth of S. aureus. In addition, bMECs treated with E2 show upregulated gene expression of antimicrobial molecules, such as DEFB1 (defensin beta 1), BNBD5 (bovine neutrophil beta-defensin 5), and S100A7 (psoriasin) [[60]]. These effects are achieved through the activation of transcriptional factors, such as AP-1, NF1, or ER (data unpublished) (Figure 4). These events lead to the inhibition of S. aureus internalization, presumably through the inhibition of focal adhesion kinase (FAK) (Figure 4) [[60]].

Considering the roles of epithelial cells during the IIR (Section 3.1), the combination of an anti-inflammatory environment and the antimicrobial response is essential for the maintenance of homeostatic epithelial flora. During infections, the host initiates an inflammatory response, sometimes aggravated, which results in damage to the tissue. Nevertheless, E2 in epithelial cells from all of the models described (using PAMPs or whole pathogens) inactivates inflammatory elements but activates the production of antimicrobial molecules, presumably induced via AP-1 or SP-1, thereby favoring elimination of the pathogen. In addition, the production of AMPs by the host can enhance the epithelial inflammatory response accordingly to reports that show the immunomodulatory properties of these molecules through the induction of chemotaxis, enhancing the phagocytic activity of macrophages and dendritic cells, upregulating the production of inflammatory cytokines, chemokines, and so on [[54], [61]]. Furthermore, it is important to highlight that the production of AMPs is not enough to counteract an infection, in particular infections caused by intracellular pathogens, which require of a correct inflammatory response [[62]].

5. Concluding Remarks and Future Directions

Epithelial cells constitute a fundamental part of the local inflammatory response and host defense against pathogens. Epithelium is a target of E2 effects where the hormone induces the production of antimicrobial molecules, thereby reinforcing its role as a defense barrier against microorganisms besides its immunomodulatory properties. In addition, AMPs can also enhance the IIR through the regulation of other immunomodulatory effects.

Antimicrobial and anti-inflammatory properties of E2 are highly relevant along the reproductive life of women. For example, in the middle of the menstrual cycle when E2 levels are high, women are more likely to experience infections in the lower FRT (viral, bacterial, or fungal) as consequence of reducing the production of AMPs by epithelial cells. These effects of E2 are selective in ways that vary according to its concentrations and the FRT site. Based on epidemiological data, women appear to lose their immunological advantage after menopause, since in aging, they are more susceptible to infections and to develop inflammatory diseases. However, the participation at these stages of the E2-induced antimicrobial response requires further research.

Results discussed in this review may lead to the development of new hormonal strategies that would improve and enhance the IIR of epithelial cells against infections at the different reproductive stages in women.



Ivan Medina-Estrada was supported by a scholarship from Consejo Nacional de Ciencia y Tecnología. This work was supported by grants from CIC14.1 to Alejandra Ochoa-Zarzosa and Consejo Nacional de Ciencia y Tecnología CB2016 287210.


  1. S. AbidS. XieM. Bose17β-estradiol dysregulates innate immune responses to Pseudomonas aeruginosa respiratory infection and is modulated by estrogen receptor antagonismInfection and Immunity2017851010.1128/IAI.00422-172-s2.0-8502977149328784925
  2. S. NadkarniS. McArthurOestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunityCurrent Opinion in Pharmacology201313457658110.1016/j.coph.2013.05.0072-s2.0-8488595532623731522
  3. M. V. PatelJ. V. FaheyR. M. RossollC. R. WiraInnate immunity in the vagina (part I): estradiol inhibits HBD2 and elafin secretion by human vaginal epithelial cellsAmerican Journal of Reproductive Immunology201369546347410.1111/aji.120782-s2.0-8487634358923398087
  4. M. L. TurnerJ. G. CroninG. D. HealeyI. M. SheldonEpithelial and stromal cells of bovine endometrium have roles in innate immunity and initiate inflammatory responses to bacterial lipopeptides in vitro via Toll-like receptors TLR2, TLR1, and TLR6Endocrinology201415541453146510.1210/en.2013-18222-s2.0-8489787372624437488
  5. S. WenG. CaoT. BaoModulation of ovine SBD-1 expression by 17beta-estradiol in ovine oviduct epithelial cellsBMC Veterinary Research201281p. 14310.1186/1746-6148-8-1432-s2.0-8486527973722920556
  6. J. V. FaheyJ. A. WrightL. ShenEstradiol selectively regulates innate immune function by polarized human uterine epithelial cells in cultureMucosal Immunology20081431732510.1038/mi.2008.202-s2.0-4544908527619079193
  7. P. LüthjeA. Lindén HirschbergA. BraunerEstrogenic action on innate defense mechanisms in the urinary tractMaturitas2014771323610.1016/j.maturitas.2013.10.0182-s2.0-8489174221224296328
  8. J. V. FaheyR. M. RossollC. R. WiraSex hormone regulation of anti-bacterial activity in rat uterine secretions and apical release of anti-bacterial factor(s) by uterine epithelial cells in cultureThe Journal of Steroid Biochemistry and Molecular Biology2005931596610.1016/j.jsbmb.2004.11.0022-s2.0-1464439654515748833
  9. C. R. WiraM. Rodríguez-GarcíaM. V. PatelThe role of sex hormones in immune protection of the female reproductive tractNature Reviews Immunology201515421723010.1038/nri38192-s2.0-8492571107425743222
  10. C. R. NishidaS. EverettP. R. Ortiz de MontellanoSpecificity determinants of CYP1B1 estradiol hydroxylationMolecular Pharmacology201384345145810.1124/mol.113.0877002-s2.0-8488316398523821647
  11. A. FrankL. M. BrownD. J. CleggThe role of hypothalamic estrogen receptors in metabolic regulationFrontiers in Neuroendocrinology201435455055710.1016/j.yfrne.2014.05.0022-s2.0-8490820448224882636
  12. I. LamoteE. MeyerA. M. Massart-LeënC. BurvenichSex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involutionSteroids200469314515910.1016/j.steroids.2003.12.0082-s2.0-184278988515072917
  13. L. YartL. FinotV. LollivierF. DessaugeOestradiol enhances apoptosis in bovine mammary epithelial cells in vitroJournal of Dairy Research2013800111312110.1017/S00220299120007142-s2.0-8487247649623236989
  14. J. F. ArnalC. FontaineA. Billon-GalésEstrogen receptors and endotheliumArteriosclerosis, Thrombosis, and Vascular Biology20103081506151210.1161/ATVBAHA.109.1912212-s2.0-77955144507
  15. E. E. ConnorM. J. MeyerR. W. LiM. E. Van AmburghY. R. BoisclairA. V. CapucoRegulation of gene expression in the bovine mammary gland by ovarian steroidsJournal of Dairy Science200790E55E6510.3168/jds.2006-4662-s2.0-3444726723517517752
  16. E. R. ProssnitzJ. B. ArterburnL. A. SklarGPR30: a G protein-coupled receptor for estrogenMolecular and Cellular Endocrinology2007265-26613814210.1016/j.mce.2006.12.0102-s2.0-3384702872117222505
  17. K. YakimchukM. JondalS. OkretEstrogen receptor α and β in the normal immune system and in lymphoid malignanciesMolecular and Cellular Endocrinology20133751-212112910.1016/j.mce.2013.05.0162-s2.0-8487932404223707618
  18. S. N. RomanoD. A. GorelickCrosstalk between nuclear and G protein-coupled estrogen receptorsGeneral and Comparative Endocrinology201826119019710.1016/j.ygcen.2017.04.0132-s2.0-8501902540428450143
  19. S. FarzanehA. ZarghiEstrogen receptor ligands: a review (2013–2015)Scientia Pharmaceutica201684340942710.3390/scipharm840304092-s2.0-8499208858028117309
  20. I. BaroneL. BruscoS. A. W. FuquaEstrogen receptor mutations and changes in downstream gene expression and signalingClinical Cancer Research201016102702270810.1158/1078-0432.CCR-09-17532-s2.0-7795239792920427689
  21. A. W. BellRegulation of organic nutrient metabolism during transition from late pregnancy to early lactationJournal of Animal Science19957392804281910.2527/1995.7392804x8582872
  22. I. LamoteE. MeyerA. De KetelaereL. DuchateauC. BurvenichInfluence of sex steroids on the viability and CD11b, CD18 and CD47 expression of blood neutrophils from dairy cows in the last month of gestationVeterinary Research2006371617410.1051/vetres:20050382-s2.0-3034446206916336925
  23. N. HeldringA. PikeS. AnderssonEstrogen receptors: how do they signal and what are their targetsPhysiological Reviews200787390593110.1152/physrev.00026.20062-s2.0-3444752333917615392
  24. C. JiangJ. GuoZ. WangDecursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cellsBreast Cancer Research200796p. R7710.1186/bcr17902-s2.0-4034911456217986353
  25. A. TamS. WadsworthD. DorscheidS.-F. P. ManD. D. SinEstradiol increases mucus synthesis in bronchial epithelial cellsPLoS One201496, article e10063310.1371/journal.pone.01006332-s2.0-8490354297524964096
  26. S. KovatsEstrogen receptors regulate innate immune cells and signaling pathwaysCellular Immunology20152942636910.1016/j.cellimm.2015.01.0182-s2.0-8493305332925682174
  27. G. M. BartonA calculated response: control of inflammation by the innate immune systemJournal of Clinical Investigation2008118241342010.1172/JCI344312-s2.0-3884913304418246191
  28. S. L. KleinK. L. FlanaganSex differences in immune responsesNature Reviews Immunology2016161062663810.1038/nri.2016.902-s2.0-8498303603727546235
  29. E. CalcagniI. ElenkovStress system activity, innate and T helper cytokines, and susceptibility to immune-related diseasesAnnals of the New York Academy of Sciences200610691627610.1196/annals.1351.0062-s2.0-3374561607616855135
  30. J. RovedH. WesterdahlD. HasselquistSex differences in immune responses: hormonal effects, antagonistic selection, and evolutionary consequencesHormones and Behavior2017889510510.1016/j.yhbeh.2016.11.0172-s2.0-8500819662627956226
  31. Z. SpolaricsG. PeñaY. QinR. J. DonnellyD. H. LivingstonInherent X-linked genetic variability and cellular mosaicism unique to females contribute to sex-related differences in the innate immune responseFrontiers in Immunology20178p. 145510.3389/fimmu.2017.014552-s2.0-85034098951
  32. C. Giefing-KröllP. BergerG. LepperdingerB. Grubeck-LoebensteinHow sex and age affect immune responses, susceptibility to infections, and response to vaccinationAging Cell201514330932110.1111/acel.123262-s2.0-8492791198925720438
  33. F. AbdiH. MobediN. MosaffaM. DolatianF. Ramezani TehraniEffects of hormone replacement therapy on immunological factors in the postmenopausal periodClimacteric201619323423910.3109/13697137.2016.11641362-s2.0-8496392897727086591
  34. P. J. SansonettiTo be or not to be a pathogen: that is the mucosally relevant questionMucosal Immunology20114181410.1038/mi.2010.772-s2.0-7865084352221150896
  35. K. F. RossM. C. HerzbergAutonomous immunity in mucosal epithelial cells: fortifying the barrier against infectionMicrobes and Infection201618638739810.1016/j.micinf.2016.03.0082-s2.0-8496186447727005450
  36. S. B. RasmussenL. S. ReinertS. R. PaludanInnate recognition of intracellular pathogens: detection and activation of the first line of defenseAPMIS20091175-632333710.1111/j.1600-0463.2009.02456.x2-s2.0-6534916227819400860
  37. R. P. SchleimerA. KatoR. KernD. KupermanP. C. AvilaEpithelium: at the interface of innate and adaptive immune responsesThe Journal of Allergy and Clinical Immunology200712061279128410.1016/j.jaci.2007.08.0462-s2.0-3674904099817949801
  38. X. HuJ. ChenL. WangL. B. IvashkivCrosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activationJournal of Leukocyte Biology200782223724310.1189/jlb.12067632-s2.0-3454773657217502339
  39. D. SchamsS. KohlenbergW. AmselgruberB. BerishaM. W. PfafflF. SinowatzExpression and localisation of oestrogen and progesterone receptors in the bovine mammary gland during development, function and involutionJournal of Endocrinology2003177230531710.1677/joe.0.17703052-s2.0-003813705212740019
  40. A. SobolewskaM. GajewskaJ. ZarzynskaB. GajkowskaT. MotylIGF-I, EGF, and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathwayEuropean Journal of Cell Biology200988211713010.1016/j.ejcb.2008.09.0042-s2.0-5764911201719013662
  41. W. WinuthayanonS. L. LierzK. C. DelarosaJuxtacrine activity of estrogen receptor α in uterine stromal cells is necessary for estrogen-induced epithelial cell proliferationScientific Reports201771p. 837710.1038/s41598-017-07728-12-s2.0-8502784893228827707
  42. S. C. HewittL. LiS. A. GrimmResearch resource: whole-genome estrogen receptor α binding in mouse uterine tissue revealed by ChIP-seqMolecular Endocrinology201226588789810.1210/me.2011-13112-s2.0-8486036495122446102
  43. G. R. CunhaP. S. CookeT. KuritaRole of stromal-epithelial interactions in hormonal responsesArchives of Histology and Cytology200467541743410.1679/aohc.67.4172-s2.0-1584442617315781983
  44. R. KowsarN. HambruchJ. LiuT. ShimizuC. PfarrerA. MiyamotoRegulation of innate immune function in bovine oviduct epithelial cells in culture: the homeostatic role of epithelial cells in balancing Th1/Th2 responseJournal of Reproduction and Development201359547047810.1262/jrd.2013-0362-s2.0-8488664234623800958
  45. S. AyehunieA. IslamC. CannonCharacterization of a hormone-responsive organotypic human vaginal tissue model: morphologic and immunologic effectsReproductive Sciences201522898099010.1177/19337191155709062-s2.0-8493753902325676577
  46. K. AikawaT. SuginoS. MatsumotoP. ChichesterC. WhitbeckR. M. LevinThe effect of ovariectomy and estradiol on rabbit bladder smooth muscle contraction and morphologyThe Journal of Urology2003170263463710.1097/01.ju.0000068723.05004.ca12853846
  47. R. RazY. GennesinJ. WasserRecurrent urinary tract infections in postmenopausal womenClinical Infectious Diseases200030115215610.1086/3135962-s2.0-003395801310619744
  48. D. D. BannermanM. J. PaapeJ.-W. LeeX. ZhaoJ. C. HopeP. RainardEscherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infectionClinical and Vaccine Immunology200411346347210.1128/CDLI.11.3.463-472.20042-s2.0-244267542515138171
  49. M. A. Crane-GodreauC. R. WiraEffects of estradiol on lipopolysaccharide and Pam3Cys stimulation of CCL20/macrophage inflammatory protein 3 alpha and tumor necrosis factor alpha production by uterine epithelial cells in cultureInfection and Immunity20057374231423710.1128/IAI.73.7.4231-4237.20052-s2.0-2154447972115972514
  50. T. HirataY. OsugaK. HamasakiExpression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycleJournal of Reproductive Immunology2007741-2536010.1016/j.jri.2006.11.0042-s2.0-3424762017017292969
  51. M. J. LesmeisterR. L. JorgensonS. L. YoungM. L. Misfeldt17Beta-estradiol suppresses TLR3-induced cytokine and chemokine production in endometrial epithelial cellsReproductive Biology and Endocrinology200531p. 7410.1186/1477-7827-3-742-s2.0-3054444397116384532
  52. D. XingS. OparilH. YuEstrogen modulates NFκB signaling by enhancing IκBα levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-βPLoS One201276, article e3689010.1371/journal.pone.00368902-s2.0-8486251793422723832
  53. B. VillaggioS. SoldanoM. Cutolo1,25-dihydroxyvitamin D3 downregulates aromatase expression and inflammatory cytokines in human macrophagesClinical and Experimental Rheumatology201230693493823253631
  54. V. Díaz-MurilloI. Medina-EstradaJ. E. López-MezaA. Ochoa-ZarzosaDefensin γ-thionin from Capsicum chinense has immunomodulatory effects on bovine mammary epithelial cells during Staphylococcus aureus internalizationPeptides20167810911810.1016/j.peptides.2016.02.0082-s2.0-8496088801126939717
  55. J. H. HanM. S. KimM. Y. LeeModulation of human β-defensin-2 expression by 17β-estradiol and progesterone in vaginal epithelial cellsCytokine201049220921410.1016/j.cyto.2009.09.0052-s2.0-7364912491619819163
  56. L. SchaeferA. BabelovaE. KissThe matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophagesThe Journal of Clinical Investigation200511582223223310.1172/JCI237552-s2.0-2364445684916025156
  57. G. SobollM. A. Crane-GodreauM. A. LyimoC. R. WiraEffect of oestradiol on PAMP-mediated CCL20/MIP-3α production by mouse uterine epithelial cells in cultureImmunology2006118218519410.1111/j.1365-2567.2006.02353.x2-s2.0-3364655022016771853
  58. G. K. BestT. O. AbneyJ. M. KlingJ. J. KirklandD. F. ScottHormonal influence on experimental infections by a toxic shock strain of Staphylococcus aureusInfection and Immunity19865213313333957430
  59. P. LüthjeH. BraunerN. L. RamosEstrogen supports urothelial defense mechanismsScience Translational Medicine20135190p. 190ra8010.1126/scitranslmed.30055742-s2.0-8488055060123785036
  60. I. Medina-EstradaJ. E. López-MezaA. Ochoa-ZarzosaAnti-inflammatory and antimicrobial effects of estradiol in bovine mammary epithelial cells during Staphylococcus aureus internalizationMediators of Inflammation2016201616612050910.1155/2016/61205092-s2.0-84962325612
  61. E. F. HaneyR. E. W. HancockPeptide design for antimicrobial and immunomodulatory applicationsBiopolymers2013100657258310.1002/bip.222502-s2.0-8488604039923553602
  62. B. SchittekThe antimicrobial skin barrier in patients with atopic dermatitisCurrent Problems in Dermatology201141546710.1159/0003232962-s2.0-8492594696321576947
  63. K. EllwangerE. BeckerI. KienesThe NLR family pyrin domain–containing 11 protein contributes to the regulation of inflammatory signalingJournal of Biological Chemistry201829382701271010.1074/jbc.RA117.0001522-s2.0-8504244881929301940
  64. M. GürsoyU. K. GürsoyA. LiukkonenT. KaukoS. PenkkalaE. KönönenSalivary antimicrobial defensins in pregnancyJournal of Clinical Periodontology2016431080781510.1111/jcpe.125812-s2.0-8498591094827191801
  65. E. VegetoS. BelcreditoS. EtteriEstrogen receptor-α mediates the brain antiinflammatory activity of estradiolProceedings of the National Academy of Sciences of the United States of America2003100169614961910.1073/pnas.15319571002-s2.0-004192255512878732
The underlying source XML for this text is taken from The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as bacterial infectious disease.