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

Figure 3

Anti-inflammatory and antibacterial effects of E2 in epithelial cells. E2 mediates its effects in epithelium by binding to intracellular receptors (ERs), leading to the translocation of hormone-ER (ER phosphorylate) complexes into the nucleus where they modulate gene transcription through binding to estrogen-responsive elements (EREs) on DNA (5GGTCAnnnTGACC-3 consensus sequence). There is another type of ER, namely, G protein-coupled receptor 30 (GPR30), which binds E2, tamoxifen, and ICI 182780 (Fulvestrant). This receptor promotes the activation of epidermal growth factor receptor (EGFR) and mediates signaling in breast, endometrial, and thyroid cancer cells. This receptor activates signaling pathways in the cytosol and at the plasma membrane [18]. However, most of the molecular targets activated by GPR30 located at the plasma membrane during infections are unknown. GPR30 also has effects on the IIR associated with nongenomic responses (e.g., nitric oxide production). When cells are infected by bacteria, they trigger the activation of proinflammatory signaling pathways, mainly depending on TLRs. These pathways (described above) promote the production of proinflammatory elements [16]. However, E2 can modulate these pathways, influencing the IIR and decreasing the proinflammatory elements by blocking the activation of transcriptional factors, such NF-κB (canonical inflammatory pathway), ultimately resulting in the downregulation of IL-1β, IL-6, and TNF-α gene expression. In contrast, the E2-ER complex mainly induces the gene expression of AMPs, such as defensins, and promotes an anti-inflammatory environment by inducing interleukin-10 (IL-10) gene expression. Gene expression regulated by E2 depends on the concentrations of the hormone and the interaction with pathogenic bacteria. It is well known that E2 reverses the inflammatory effects (association with bacteria and proinflammatory cytokines) and promotes an anti-inflammatory environment [8, 60, 64, 65].