IL-6改善反复自然流产小鼠妊娠结局的机制

Mechanism of IL-6 improving pregnancy outcome in mice with recurrent spontaneous abortion

目的:研究在孕早期使用IL-6能否改善复发性流产(RSA)小鼠的妊娠结局及其相关机制,为临床治疗RSA提供新思路。方法:构建CBA/J×DBA/2小鼠RSA模型,将受孕后的雌鼠随机分为5组:control组、0.1 ng/ml IL-6组,1 ng/ml IL-6组、10 ng/ml IL-6组及100 ng/ml IL-6组,control组不注射IL-6,其余各组分别于妊娠0.5 d注射不同浓度IL-6,于孕13.5 d处死孕鼠,计算胚胎吸收率,取胎盘组织,Western blot检测该组织中IL-6和吲哚胺2,3-双加氧酶(IDO)的表达情况。结果:0.1 ng/ml IL-6组、1 ng/ml IL-6组、10 ng/ml IL-6组及100 ng/ml IL-6组胚胎吸收率均显著低于对照组(P=0.0024、P=0.0070、P=0.0270、P=0.0310)。外源性注射的IL-6与RSA小鼠胎盘组织中表达的IL-6呈正相关(r=0.791,P=0.000052),外源性注射IL-6的浓度为0~1 ng/ml,外源性注射IL-6的浓度与胎盘组织中IDO的表达呈正相关(r=0.868,P<0.0001),胎盘组织中IL-6与IDO的表达呈正相关(r=0.982,P<0.0001),外源性注射IL-6的浓度为1~100 ng/ml,外源性IL-6的浓度与IDO的表达呈负相关(r=-0.725,P=0.002),胎盘组织中IL-6与IDO的表达呈负相关(r=-0.972,P<0.0001)。结论:RSA小鼠一次性腹腔注射特定浓度的外源性IL-6可降低该小鼠的胚胎吸收率并改善其妊娠结局,可能的机制是外源性IL-6持久诱导胎盘组织中IL-6和IDO表达,胎盘组织中IDO表达是否增加可作为特定浓度IL-6对妊娠是否具有保护作用的标志。

Objective:To investigate whether IL-6 using in early pregnancy can improve the pregnancy outcome of recurrent spontaneous abortion(RSA)mice and its relevant mechanism,providing new ideas for RSA clinical treatment.Methods:CBA/J×DBA/2 RSA model mice were constructed,and randomly divided the pregnant mice into five groups:control group,0.1 ng/ml IL-6 group,1 ng/ml IL-6 group,10 ng/ml IL-6 group and 100 ng/ml IL-6 group.IL-6 was not injected in control group,while different concentrations of IL-6 were respectively injected into other groups on the 0.5 day of pregnancy.Pregnant rats were killed at 13.5 d and the embryo loss rate was calculated,the placental tissue was taked out,and expressions of IL-6 and indoleamine 2,3-dioxygenase(IDO)in tissues were detected by Western blot.Results:Embryo absorption rates of 0.1 ng/ml IL-6 group,1 ng/ml IL-6 group,10 ng/ml IL-6 group and 100 ng/ml IL-6 group were obviously lower than that in control group(P=0.0024,P=0.0070,P=0.0270,P=0.0310).IL-6 of exogenous injection was positive correlated with that expressed in mice placental tissue(r=0.791,P=0.000052).IL-6 concentration of exogenous injection was between 0~1 ng/ml,which was positively correlated with IDO expression in placental tissue(r=0.868,P<0.0001),IL-6 was positively correlated with IDO expressed in placental tissue(r=0.982,P<0.0001).IL-6 concentration of exogenous injection was between 1~100 ng/ml,which was inversely correlated with IDO expression(r=-0.725,P=0.002),and IL-6 was inversely correlated with IDO expressed in placental tissue(r=-0.972,P<0.0001).Conclusion:A single intraperitoneal injection of specific concentration of exogenous IL-6 to RSA mice can reduce embryo absorption rate of mice and modify their pregnancy outcome,which possible mechanism is the exogenous IL-6 induces expressions of IL-6 and IDO for a long term.Whether the IDO expression in placental tissue increase or not can be regarded as a mark for whether the specific concentration IL-6 can protect the pregnancy or not.