Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia.
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russia.
Steroids. 2019 May;145:5-18. doi: 10.1016/j.steroids.2019.02.009. Epub 2019 Feb 10.
Progesterone (P4) and its analogues regulate various reproductive processes, such as ovulation, implantation, pregnancy maintenance and delivery. In these processes, an important role is played by the immune cells recruited to the female reproductive organs and tissues, where they are exposed to the action of P4. Progestins regulate cellular processes, acting through nuclear steroid receptors (nSRs), membrane P4 receptors (mPRs), and through the sensors. It remains unclear, what type of receptors is used by P4 and its derivatives to exert their effect on the immune cells and how similar their effects are in different types of these cells. We have previously synthesized new progesterone derivatives, among which two selective mPRs ligands, not interacting with nSRs were identified. The objective of this study was to examine the effects of P4 and new selective mPRs ligands on the expression of pro- and anti-inflammatory cytokines in activated human peripheral blood mononuclear cells (PBMCs), THP-1 monocyte cells, and Jurkat T cells. It was demonstrated that the action of P4 and selective ligands was unidirectional, but in different types of the immune cells, their effects were different, and sometimes even opposite. In PBMCs, exposure to these steroids resulted in the increase of mRNA and secreted protein levels of IL-1β, TNFα, and IL-6 cytokines, as well as in the increase of INFγ mRNA level, decrease of IL-2 mRNA level, increase of TGFβ mRNA level, and decrease of IL-4 mRNA and IL-10 secreted protein levels. In monocytes, similarly to PBMCs, expression of IL-1β and TNFα mRNA was increased, but expression of IL-10 was also increased, and the TGFβ expression statistically significantly remained the same. In Jurkat T cells, expression of IL-2 and TNFα mRNA decreased, while expression of IL-10 increased, and expression of TGFβ did not change. Thus, progestins act on the immune cells through mPRs and have both pro- and anti-inflammatory effects, depending on the phenotypes of these cells. The data obtained are important for understanding the complexity of the immune system regulation by progestins, which depends on the type of the immune cells and individual characteristics of the immune system.
孕激素（P4）及其类似物调节各种生殖过程，如排卵、着床、妊娠维持和分娩。在这些过程中，募集到女性生殖器官和组织中的免疫细胞发挥着重要作用，它们在这些组织中暴露于 P4 的作用下。孕激素通过核甾体受体（nSR）、膜 P4 受体（mPR）和传感器调节细胞过程。目前尚不清楚 P4 及其衍生物是通过哪种类型的受体对免疫细胞发挥作用，以及它们在不同类型的免疫细胞中的作用有何相似之处。我们之前合成了新的孕激素衍生物，其中鉴定出两种不与 nSR 相互作用的选择性 mPR 配体。本研究的目的是研究 P4 和新的选择性 mPR 配体对激活的人外周血单核细胞（PBMCs）、THP-1 单核细胞和 Jurkat T 细胞中促炎和抗炎细胞因子表达的影响。结果表明，P4 和选择性配体的作用是单向的，但在不同类型的免疫细胞中，它们的作用不同，有时甚至相反。在 PBMCs 中，这些类固醇的暴露导致 IL-1β、TNFα 和 IL-6 细胞因子的 mRNA 和分泌蛋白水平增加，以及 INFγ mRNA 水平增加、IL-2 mRNA 水平降低、TGFβ mRNA 水平增加和 IL-4 mRNA 和 IL-10 分泌蛋白水平降低。在单核细胞中，与 PBMCs 相似，IL-1β 和 TNFα mRNA 的表达增加，但 IL-10 的表达也增加，TGFβ 的表达统计学上保持不变。在 Jurkat T 细胞中，IL-2 和 TNFα mRNA 的表达减少，而 IL-10 的表达增加，TGFβ 的表达没有变化。因此，孕激素通过 mPR 作用于免疫细胞，具有促炎和抗炎作用，这取决于这些细胞的表型。这些数据对于理解孕激素对免疫系统的调节的复杂性非常重要，这取决于免疫细胞的类型和免疫系统的个体特征。
