Mazzeo D, Viganó P, Di Blasio A M, Sinigaglia F, Vignali M, Panina-Bordignon P
Roche Milano Ricerche, Milan, Italy.
J Clin Endocrinol Metab. 1998 Mar;83(3):911-6. doi: 10.1210/jcem.83.3.4612.
An alteration of immune recognition and killing of misplaced endometrial cells, refluxed with menstrual debris in ectopic sites, has been claimed to be responsible for the initiation and progression of endometriosis. In particular, current evidence emphasizes the role of natural killer (NK) cells as potential effectors of peritoneal immune surveillance. Interleukin-12 (IL-12), a heterodimeric cytokine composed of p40 and p35 chains, has potent regulatory effects on NK cell growth and function. The purpose of this study was to evaluate whether this cytokine may also have a role in the specific cytolytic NK cell response toward endometrial antigens. To this aim, concentrations of IL-12 and its free p40 subunit were determined in peritoneal fluid of 33 patients with endometriosis and 40 women without laparoscopic evidence of the disease. Similar concentrations of IL-12, but significantly higher levels of free p40, were present in peritoneal fluid of patients with endometriosis compared to those in women without the disease. We also observed that the IL-12 plus free p40/IL-12 ratio increased with the severity of the disease. Moreover, we investigated whether incubation of NK cells with heterodimeric IL-12 and/or p40 has any effect on NK cell-mediated lysis of endometrial cells. NK cells pretreated with heterodimeric IL-12 exhibited an enhanced cytotoxic response toward endometrial targets. This IL-12-induced cytotoxicity could be abrogated by the p40 subunit in a specific and dose-dependent manner. The p40 inhibitory effect was mediated by down-regulation of IL-12 high affinity binding sites on NK cells, as we observed inhibition of surface IL-12 receptor beta1-chain expression, a decrease in IL-12-binding capacity, and inhibition of phosphorylation of STAT4 (signal transducer and activator of transcription) protein. These data suggest that the excess of p40 present in peritoneal fluid of patients with endometriosis may be related to the NK cell defect associated with the disease. Moreover, IL-12 could be a potential specific agent able to correct the p40-induced defect in vivo.
异位的子宫内膜细胞随月经碎片逆流至异位部位，免疫识别及杀伤这些异位细胞的改变被认为是子宫内膜异位症发生和发展的原因。特别是，目前的证据强调自然杀伤（NK）细胞作为腹膜免疫监视潜在效应细胞的作用。白细胞介素-12（IL-12）是一种由p40和p35链组成的异二聚体细胞因子，对NK细胞的生长和功能具有强大的调节作用。本研究的目的是评估这种细胞因子是否也在NK细胞对子宫内膜抗原的特异性溶细胞反应中发挥作用。为此，测定了33例子宫内膜异位症患者和40例无腹腔镜疾病证据的女性腹膜液中IL-12及其游离p40亚基的浓度。与无该疾病的女性相比，子宫内膜异位症患者腹膜液中IL-12浓度相似，但游离p40水平显著更高。我们还观察到，IL-12加游离p40/IL-12的比值随疾病严重程度增加。此外，我们研究了用异二聚体IL-12和/或p40孵育NK细胞是否对NK细胞介导的子宫内膜细胞裂解有任何影响。用异二聚体IL-12预处理的NK细胞对子宫内膜靶标的细胞毒性反应增强。这种IL-12诱导的细胞毒性可被p40亚基以特异性和剂量依赖性方式消除。p40的抑制作用是通过下调NK细胞上IL-12高亲和力结合位点介导的，因为我们观察到表面IL-12受体β1链表达受到抑制、IL-12结合能力降低以及信号转导和转录激活因子4（STAT4）蛋白磷酸化受到抑制。这些数据表明，子宫内膜异位症患者腹膜液中存在的过量p40可能与该疾病相关的NK细胞缺陷有关。此外，IL-12可能是一种能够在体内纠正p40诱导缺陷的潜在特异性药物。
