McCracken Sharon A, Hadfield Katrina, Rahimi Zolaikha, Gallery Eileen D, Morris Jonathan M
Perinatal Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, Australia.
Eur J Immunol. 2007 May;37(5):1386-96. doi: 10.1002/eji.200636322.
The molecular mechanisms that suppress Th1 immune responses in pregnancy are unknown. We assessed the expression of the Th1 cytokine transcription factor T-bet. We isolated PBMC and T cells from non-pregnant and pregnant women and demonstrated that T-bet is specifically down-regulated in pregnancy under basal and stimulated conditions. Low levels of T-bet protein were detected in the nuclear fraction of unstimulated PBMC from non-pregnant, but not pregnant women. Nuclear levels of T-bet increased in response to PMA/ionomycin in PBMC from non-pregnant, but not pregnant women. T-bet expression was greater in whole cell lysates of stimulated CD3(+) T cells from non-pregnant relative to pregnant women. NF-kappaB is specifically down-regulated in T cells in pregnant women, resulting in suppressed expression of Th1 cytokines IL-2, IFN-gamma and TNF-alpha. In this study, down-regulation of NF-kappaB also resulted in diminished expression of T-bet. PMA induces NF-kappaB translocation, T-bet expression and IL-2, IFN-gamma and TNF-alpha production. Conversely, pre-incubation with SN50, and NF-kappaB oligodeoxyribonucleotide decoys suppressed PMA-induced NF-kappaB translocation and gene transcription, respectively, resulting in diminished T-bet expression and Th1 cytokine production. Therefore, maintenance of the cytokine environment for pregnancy success is mediated via strict regulation of Th1 immune responses, more specifically through control of NF-kappaB and T-bet transcription.
孕期抑制Th1免疫反应的分子机制尚不清楚。我们评估了Th1细胞因子转录因子T-bet的表达。我们从非孕期和孕期女性中分离出外周血单个核细胞（PBMC）和T细胞，并证明在基础和刺激条件下，T-bet在孕期会特异性下调。在非孕期女性而非孕期女性未刺激的PBMC核部分中检测到低水平的T-bet蛋白。在非孕期女性而非孕期女性的PBMC中，T-bet的核水平在佛波酯（PMA）/离子霉素刺激下会升高。相对于孕期女性，非孕期女性受刺激的CD3(+) T细胞全细胞裂解物中T-bet的表达更高。核因子κB（NF-κB）在孕期女性的T细胞中特异性下调，导致Th1细胞因子白细胞介素-2（IL-2）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）的表达受到抑制。在本研究中，NF-κB的下调也导致T-bet的表达减少。PMA诱导NF-κB易位、T-bet表达以及IL-2、IFN-γ和TNF-α的产生。相反，用SN50和NF-κB寡脱氧核糖核苷酸诱饵预孵育分别抑制了PMA诱导的NF-κB易位和基因转录，导致T-bet表达和Th1细胞因子产生减少。因此，孕期成功所需的细胞因子环境的维持是通过严格调节Th1免疫反应介导的，更具体地说是通过控制NF-κB和T-bet转录来实现的。
