McGovern Matthew, Kelly Lynne A, Finnegan Rebecca, Murphy John F, Kelleher John, Melo Ashanty M, Greene Catherine M, Molloy Eleanor J
Discipline of Paediatrics, Trinity College, the University of Dublin, Dublin, Ireland.
Trinity Translational Medicine Institute (TTMI) & Trinity Research in Childhood Centre (TRICC), Trinity College Dublin, Dublin, Ireland.
Pediatr Res. 2025 Sep 24. doi: 10.1038/s41390-025-04350-0.
Preterm infants are at increased risk of sepsis compared to adults and older children. Preterm immune cells have altered cytokine responses compared to term neonates and adults and all have sex-related differences in immunity. We examined inflammasome activation and cytokines with endotoxin and sex steroid hormones between preterm and term neonates.
Preterm (n = 40) and term (n = 32) peripheral blood samples were incubated with Lipopolysaccharide (LPS), Estradiol (E2), Progesterone (Pg) or Pam3CSK4 and biomarkers were analysed by ELISA. Inflammasome genes, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Interleukin-1 beta (IL1-β) and Absent In Melanoma 2 (AIM 2) were analysed with Taqman RT-PCR.
IL-1β cytokine expression was reduced by female sex hormones and notably the effect of estradiol was greatest in the preterm population. Female preterm neonates were more responsive to the anti-inflammatory effect of progesterone than male preterm infants. Term neonates had higher IL-1β, IL-18 and IL-1RA expression than preterm infants. Overall, in preterms, E2 and Pg lowered cytokine expression levels. Inflammasome gene expression profiles did not differ between preterm male and female neonates.
Sex hormones altered the expression of multiple cytokines, and cytokine responses differ by sex. Gestation plays an important role in the inflammatory response, and we note term infants have a more robust profile while preterm infants are more responsive to hormonal stimulus. Female sex hormones have an important role in modulating neonatal immune response and may contribute to the female immune advantage.
Female sex hormones play an important role in modulating the neonatal immune response. This is reflected clinically by better bacterial clearance and improved sepsis outcome in females. This study aims to test the hypothesis that male and female neonates differ in their cytokine and inflammasome response and in response to endotoxin and sex steroid hormones. In preterm infants there is a sex difference in IL-1b responses which is observed rapidly following endotoxin stimulation. Differing immune responses according to sex has implications for future clinical application. Further work to characterise these sex differences may help in guiding therapy during sepsis.
与成人和大龄儿童相比，早产儿患败血症的风险更高。与足月儿和成人相比，早产儿的免疫细胞细胞因子反应有所改变，且在免疫方面均存在性别差异。我们研究了早产儿和足月儿之间炎性小体的激活情况以及内毒素和性类固醇激素对细胞因子的影响。
将早产儿（n = 40）和足月儿（n = 32）的外周血样本与脂多糖（LPS）、雌二醇（E2）、孕酮（Pg）或Pam3CSK4一起孵育，并用酶联免疫吸附测定法（ELISA）分析生物标志物。采用Taqman逆转录聚合酶链反应（RT-PCR）分析炎性小体基因，即含NLR家族pyrin结构域3（NLRP3）、凋亡相关斑点样蛋白（ASC）、白细胞介素-1β（IL1-β）和黑素瘤缺失因子2（AIM2）。
女性性激素可降低IL-1β细胞因子的表达，尤其是雌二醇对早产儿群体的影响最大。与男性早产儿相比，女性早产儿对孕酮的抗炎作用更敏感。足月儿的IL-1β、IL-18和IL-1RA表达高于早产儿。总体而言，在早产儿中，E2和Pg降低了细胞因子表达水平。早产儿男性和女性新生儿的炎性小体基因表达谱没有差异。
性激素改变了多种细胞因子的表达，且细胞因子反应存在性别差异。孕周在炎症反应中起重要作用，我们注意到足月儿的炎症反应更强，而早产儿对激素刺激更敏感。女性性激素在调节新生儿免疫反应中起重要作用，可能是女性免疫优势的原因之一。
女性性激素在调节新生儿免疫反应中起重要作用。这在临床上表现为女性细菌清除能力更强，败血症预后更好。本研究旨在验证以下假设：男性和女性新生儿在细胞因子和炎性小体反应以及对内毒素和性类固醇激素的反应方面存在差异。在内毒素刺激后，早产儿的IL-1b反应存在性别差异。根据性别不同的免疫反应对未来临床应用具有重要意义。进一步研究这些性别差异可能有助于指导败血症治疗。
