Laboratory of Dendritic Cell Biology, Department of Microbiology-Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Division of Rheumatology, Joseph Jr. Stokes Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Mediators Inflamm. 2017;2017:2034348. doi: 10.1155/2017/2034348. Epub 2017 Jul 25.
Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNF) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested.
性激素会影响免疫反应，并可能促进自身免疫。内分泌干扰化学物质，如双酚 A（BPA），可能会模拟它们的免疫作用。传统的树突状细胞（cDC）是在病原体或受损组织发出的危险信号激活后，启动免疫反应的关键起始者，通过触发 Toll 样受体（TLR）来实现。我们在没有雌激素的情况下体外生成了小鼠 cDC，并测量了外源性添加的雌激素或 BPA 对其分化和激活的影响，这些激活是通过 TLR 配体 LPS 和 CpG 触发的。雌激素增强了 GM-CSF 依赖性 cDC 从骨髓前体中的体外分化，而选择性雌激素受体调节剂（SERMs）他莫昔芬和氟维司群阻断了这些作用。此外，雌激素增强了 TLR9 配体 CpG 刺激时共刺激分子和促炎细胞因子（IL-12p70 和 TNF）的上调，而对 LPS 的反应则较少依赖于雌激素。这些作用部分可以通过雌激素依赖性 TLR9 表达调节来解释。BPA 不能促进 cDC 在 TLR 刺激下的分化或激活。我们的研究结果表明，雌激素通过增加 DC 的激活来促进免疫反应，对 TLR9 的刺激比对 TLR4 的刺激具有更大的影响，同时强调了雌激素对 DC 培养中的影响，而 BPA 在我们测试的 DC 功能中没有模拟雌激素的作用。
