Interleukin 10 regulates inflammatory cytokine synthesis to protect against lipopolysaccharide-induced abortion and fetal growth restriction in mice
Interleukin 10 regulates inflammatory cytokine synthesis to protect against lipopolysaccharide-induced abortion and fetal growth restriction in mice
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DOI：
10.1095/biolreprod.106.056143
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发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Skinner, Rebecca J.
中科院分区：
文献类型：
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作者：
Robertson, Sarah A.;Care, Alison S.;Skinner, Rebecca J.
白介素 10 (IL10) 是一种有效的免疫调节细胞因子和炎症细胞因子合成抑制剂。为了评估 IL10 在妊娠中的抗炎作用，我们检查了 IL10 基因缺陷小鼠对低剂量脂多糖 (LPS) 诱导的流产的反应。当 IL10 缺失突变体 C57BI/6 (1110(-)/(-)) 和对照 (1110(+/+)) 小鼠在妊娠第 9.5 天给予低剂量 LPS 时，IL10 缺乏易导致胎儿流产，并伴有剩余存活胎儿的生长受限，100% 流产的阈值剂量减少约 10 倍。给予LPS后，与1110(+/'+)小鼠相比，1110(-)/('-)小鼠血清、子宫和胚胎组织中炎症细胞因子肿瘤坏死因子-α(TNFA)和IL6显着增加，妊娠组织中Tnfa和116 mRNA的局部合成增加。 IL11A 和 IL12p40 在血清和妊娠组织中同样升高，而干扰素 γ (IFNG) 和可溶性 TNFRII 含量在没有 IL10 的情况下没有变化。重组IL10挽救了II10(-/-)小鼠对LPS诱导的胎儿丢失的易感性增加，但没有改善1110(+/+)小鼠的结果。 IL10 基因型还影响小鼠对 TNFA 拮抗剂依那西普的反应。中度或高剂量的依那西普可部分缓解 1110(-/-) 小鼠的胎儿丢失，而 1110(+/+) 小鼠对高剂量依那西普无效，这与依那西普治疗后 TNFA 生物利用度的 IL10 状态减弱一致。这些数据表明，IL10 通过下调促炎细胞因子 TNFA、IL6、ILIA 和 IL12 的表达来调节对炎症刺激的抵抗力，从而防止植入部位出现炎症诱导的病理。
Interleukin 10 (IL10) is a potent immune-regulating cytokine and inhibitor of inflammatory cytokine synthesis. To evaluate the anti-inflammatory role of IL10 in pregnancy, the response of genetically IL10-deficient mice to low-dose lipopolysaccharide (LPS)-induced abortion was examined. When IL10-null mutant C57BI/6 (1110(-)/(-)) and control (1110(+/+)) mice were administered low-dose LPS on Day 9.5 of gestation, IL10 deficiency predisposed to fetal loss accompanied by growth restriction in remaining viable fetuses, with an approximately 10-fold reduction in the threshold dose for 100% abortion. After LPS administration, inflammatory cytokines tumor necrosis factor-alpha (TNFA) and IL6 were markedly increased in serum, uterine, and conceptus tissues in 1110(-)/('-) mice compared with 1110(+/'+) mice, with elevated local synthesis of Tnfa and 116 mRNAs in the gestational tissues. IL11A and IL12p40 were similarly elevated in serum and gestational tissues, whereas interferon gamma (IFNG) and soluble TNFRII content were unchanged in the absence of IL10. Recombinant IL10 rescued the increased susceptibility to LPS-induced fetal loss in II10(-/-) mice but did not improve outcomes in 1110(+/+) mice. IL10 genotype also influenced the responsiveness of mice to a TNFA antagonist, etanercept. Fetal loss in 1110(-/-) mice was partly alleviated by moderate or high doses of etanercept, whereas 1110(+/+) mice were refractory to high-dose etanercept, consistent with attenuation by IL10 status of TNFA bioavailability after etanercept treatment. These data show that IL10 modulates resistance to inflammatory stimuli by downregulating expression of proinflammatory cytokines TNFA, IL6, ILIA, and IL12, acting to protect against inflammation-induced pathology in the implantation site.