Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, IA, USA; Iowa Inflammation Program, University of Iowa, Iowa City, IA, USA.
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, USA; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Kaiser Permanente, Roseville, CA, USA.
Cytokine. 2023 Jul;167:156210. doi: 10.1016/j.cyto.2023.156210. Epub 2023 Apr 30.
The induction of maternal inflammation in mice leads to fetal injury that is believed to be IL-6 dependent. The fetal inflammatory response, defined by elevated fetal or amniotic fluid IL-6, has been described as a potential mechanism for subsequent fetal injury. The role of maternal IL-6 production and signaling in the fetal IL-6 response is currently unclear.
Genetic and anti-IL-6 antibody strategies were used to systematically block the maternal IL-6 response during inflammation. Chorioamnionitis was induced using intraperitoneal injection of lipopolysaccharide (LPS) at mid gestation (E14.5) and late gestation (E18.5). This model was used in pregnant C57Bl/6 dams, IL6 dams, C57Bl/6 dams treated with anti-IL-6 (blocks both classical and trans-signaling) or anti-gp130 antibodies (blocks trans-signaling only) and IL6 dams. Six hours following LPS injection, maternal serum, placental tissue, amniotic fluid and fetal tissue or serum were collected. A bead-based multiplex assay was used to evaluate levels of IL-6, KC, IL-1β, TNF, IL-10, IL-22, IFN-γ, IL-13 and IL-17A.
Chorioamnionitis in C57Bl/6 dams was characterized by elevated maternal serum levels of IL-6, KC and IL-22 with litter loss during mid gestation. The fetal response to maternal inflammation in C57Bl/6 mice was primarily characterized by elevated levels of IL-6, KC and IL-22 in the placenta, amniotic fluid and fetus during both mid and late gestation. A global IL-6 knockout (IL6) eradicated the maternal, placental, amniotic fluid and fetal IL-6 response to LPS during mid and late gestation and improved litter survival, while minimally influencing the KC or IL-22 responses. Blocking maternal classical IL-6 signaling in C57Bl/6 dams at the time of LPS exposure diminished the maternal, placental, amniotic fluid and fetal IL-6 response during mid and late gestation, while blocking maternal IL-6 trans-signaling only affected fetal IL-6 expression. To evaluate whether maternal IL-6 was crossing the placenta and reaching the fetus, IL-6 dams were utilized in the chorioamnionitis model. IL-6 dams mounted a systemic inflammatory response following injection with LPS, characterized by elevated IL-6, KC and IL-22. IL-6 pups born to IL6 dams had decreased amniotic fluid levels of IL-6 and undetectable levels of fetal IL-6 compared to IL-6 littermate controls.
The fetal response to systemic maternal inflammation is dependent upon maternal IL-6 signaling, but maternal IL-6 is not crossing the placenta and reaching the fetus at detectable levels.
在小鼠中诱导母体炎症会导致胎儿损伤，据信这与白细胞介素 6（IL-6）有关。胎儿炎症反应通过升高胎儿或羊水 IL-6 来定义，被认为是随后胎儿损伤的潜在机制。目前尚不清楚母体 IL-6 产生和信号转导在胎儿 IL-6 反应中的作用。
使用基因和抗 IL-6 抗体策略在炎症期间系统阻断母体 IL-6 反应。在妊娠中期（E14.5）和妊娠晚期（E18.5）通过腹腔内注射脂多糖（LPS）诱导绒毛膜羊膜炎。该模型用于怀孕 C57Bl/6 母鼠、IL6 母鼠、用抗 IL-6（阻断经典和转导信号）或抗 gp130 抗体（仅阻断转导信号）处理的 C57Bl/6 母鼠和 IL6 母鼠。在 LPS 注射后 6 小时，收集母体血清、胎盘组织、羊水和胎儿组织或血清。使用基于珠的多重分析来评估 IL-6、KC、IL-1β、TNF、IL-10、IL-22、IFN-γ、IL-13 和 IL-17A 的水平。
C57Bl/6 母鼠的绒毛膜羊膜炎表现为母体血清中 IL-6、KC 和 IL-22 水平升高，并在妊娠中期出现胎鼠丢失。C57Bl/6 小鼠母体炎症对胎儿的反应主要表现为在妊娠中期和晚期胎盘、羊水和胎儿中 IL-6、KC 和 IL-22 水平升高。在妊娠中期和晚期，全身性 IL-6 基因敲除（IL6）消除了 LPS 引起的母体、胎盘、羊水和胎儿 IL-6 反应，提高了胎鼠存活率，而对 KC 或 IL-22 反应的影响最小。在 LPS 暴露时阻断 C57Bl/6 母鼠的经典 IL-6 信号转导，降低了妊娠中期和晚期的母体、胎盘、羊水和胎儿 IL-6 反应，而仅阻断母体 IL-6 转导信号仅影响胎儿 IL-6 表达。为了评估母体 IL-6 是否穿过胎盘并到达胎儿，在绒毛膜羊膜炎模型中使用了 IL6 母鼠。IL6 母鼠在注射 LPS 后会出现全身炎症反应，表现为 IL-6、KC 和 IL-22 升高。与 IL6 同窝仔鼠相比，IL-6 母鼠所生 IL-6 仔鼠的羊水 IL-6 水平降低，且无法检测到胎儿 IL-6。
胎儿对全身母体炎症的反应依赖于母体 IL-6 信号，但母体 IL-6 不会穿过胎盘并以可检测到的水平到达胎儿。
