Expression of the heterodimeric cytokine interleukin-(IL-)12 is induced by pattern recognition receptors responding to microbial stimuli such as lipopolysaccharide (LPS) and products of the immune system such as interferon-gamma (IFN-gamma) and CD40L. The formation of bioactive IL-12 requires equimolar synthesis of p35 and p40 subunits. However, p35 expression limits the amount of IL-12 formed. Transcription of the gene for the p35 subunit of IL-12 initiates within the first exon, an alternate first exon (exon 1a), or second exon. Here we show that LPS and IFN-gamma/CD40 ligation increase the amount of total p35 mRNA in splenic adherent cells (SAC) to a similar extent. However, the exon 1 transcript was a smaller fraction of total p35 mRNA in IFN-gamma/CD40-stimulated cells than in unstimulated or LPS-stimulated cells. Despite comparable levels of total p35 mRNA, LPS-induced p35 exon 1 transcripts led to significantly more bioactive IL-12 from SAC than IFN-gamma/CD40-induced exon 1a/exon 2 transcripts as measured by ELISA. The data suggest that LPS-inducible p35 synthesis from exon 1 p35 transcripts leads to greater amount of bioactive IL-12 than IFN-gamma/CD40-induced p35 expression from alternate p35 exon 1a/exon 2 transcripts.

译文

异二聚体细胞因子白细胞介素-(IL-)12的表达由对微生物刺激 (例如脂多糖 (LPS)) 和免疫系统产物 (例如干扰素-γ (IFN-γ) 和CD40L) 做出反应的模式识别受体诱导。生物活性IL-12的形成需要等摩尔合成p35和p40亚基。然而,p35表达限制了形成的IL-12的量。IL-12的p35亚基的基因的转录在第一外显子、交替的第一外显子 (外显子1a) 或第二外显子内启动。在这里,我们显示LPS和IFN-γ/CD40连接在相似程度上增加了脾贴壁细胞 (SAC) 中总p35 mRNA的量。然而,与未刺激或LPS刺激的细胞相比,IFN-γ/CD40-stimulated细胞中的外显子1转录物在总p35mrna中的比例更小。尽管总p35 mRNA水平相当,但LPS诱导的p35外显子1转录物导致SAC的生物活性IL-12明显高于IFN-γ/CD40-induced外显子1a/外显子2转录物,如通过ELISA测量。数据表明,与来自交替的p35外显子1a/外显子2转录本的IFN-γ/CD40-induced p35表达相比,来自外显子1 p35转录本的LPS诱导的p35合成导致更多的生物活性IL-12。

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