College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, Guangzhou, 510642, China.
College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
J Steroid Biochem Mol Biol. 2021 Sep;212:105926. doi: 10.1016/j.jsbmb.2021.105926. Epub 2021 Jun 4.
The main physiological function of 17β-estradiol (E2) in vertebrates is to regulate sexual development and reproduction. In fish, especially hermaphroditic fish, estrogen is often used to aid reproduction, but it also can trigger an inflammatory response. However, the molecular mechanism for this E2-induced inflammatory reaction is not clear. In this study, we found that the ERβ-CXCL19/CXCR4-NFκB cascade regulated the E2-induced inflammatory response in the orange-spotted grouper (Epinephelus coioides). Strikingly, E2 treatment resulted in significantly high expression of inflammatory cytokines and induced phosphorylation and degradation of IκBα and translocation of NFκB subunit p65 to the nucleus in grouper spleen cells. However, the E2-induced inflammatory response could be prevented by the broad estrogen receptor (ER) ligand ICI 182,780. Moreover, the luciferase assay showed that E2 induced the inflammatory response by activating the promotor of chemokine CXCL19 through ERβ1 and ERβ2. Knockdown of CXCL19 blocked the E2-induced inflammatory response and NFκB nucleus translocation. Additionally, knockdown of chemokines CXCR4a and CXCR4b together, but not alone, blocked the E2-induced inflammatory response. The immunofluorescence assay and co-immunoprecipitation analysis showed that CXCL19 mediated the E2-induced inflammatory response by activating CXCR4a or CXCR4b. Taken together, these results showed that the ERβ-CXCL19/CXCR4-NFκB pathway mediated the E2-induced inflammatory response in grouper. These findings are valuable for future comparative immunological studies and provide a theoretical basis for mitigating the adverse reactions that occur when using E2 to help fish reproduce.
17β-雌二醇（E2）在脊椎动物中的主要生理功能是调节性发育和生殖。在鱼类中，特别是雌雄同体的鱼类中，雌激素通常被用于辅助繁殖，但它也会引发炎症反应。然而，E2 诱导炎症反应的分子机制尚不清楚。在这项研究中，我们发现 ERβ-CXCL19/CXCR4-NFκB 级联调节了橙点石斑鱼（Epinephelus coioides）中 E2 诱导的炎症反应。引人注目的是，E2 处理导致炎症细胞因子的表达显著升高，并诱导 IκBα 的磷酸化和降解以及 NFκB 亚基 p65 向细胞核易位。然而，广谱雌激素受体（ER）配体 ICI 182,780 可以预防 E2 诱导的炎症反应。此外，荧光素酶检测表明，E2 通过 ERβ1 和 ERβ2 激活趋化因子 CXCL19 的启动子诱导炎症反应。CXCL19 的敲低阻断了 E2 诱导的炎症反应和 NFκB 核易位。此外，同时敲低趋化因子 CXCR4a 和 CXCR4b，但不是单独敲低，阻断了 E2 诱导的炎症反应。免疫荧光和共免疫沉淀分析表明，CXCL19 通过激活 CXCR4a 或 CXCR4b 介导 E2 诱导的炎症反应。总之，这些结果表明 ERβ-CXCL19/CXCR4-NFκB 途径介导了石斑鱼中 E2 诱导的炎症反应。这些发现对于未来的比较免疫学研究具有重要价值，并为使用 E2 帮助鱼类繁殖时减轻不良反应提供了理论依据。
