Raynal M C, Liu Z Y, Hirano T, Mayer L, Kishimoto T, Chen-Kiang S
Brookdale Center for Molecular Biology, New York, NY 10029.
Proc Natl Acad Sci U S A. 1989 Oct;86(20):8024-8. doi: 10.1073/pnas.86.20.8024.
The molecular mechanism by which interleukin 6 (IL-6) induces terminal differentiation of B cells was investigated in a subpopulation of the clonal human B-lymphoblastoid cell line CESS selected for high density of cell surface IgG1. Induction of CESS cells with IL-6 resulted in a 15-fold preferential accumulation of secreted-specific gamma 1 (gamma 1s) mRNA but not of the alternatively processed membrane-specific gamma 1 (gamma 1m) mRNA. Similarly, microseconds mRNA but not the microns mRNA of the nonproductively rearranged mu heavy-chain allele was also increased. Accompanying the differential accumulation of gamma 1s mRNA was a 4.5-fold increase in lambda light-chain mRNA, leading to secretion of IgG1. Analyses of transcription in isolated nuclei demonstrated that transcriptional activation was the primary mechanism for quantitative increase of immunoglobulin mRNAs (5.5-fold for gamma 1 and mu and at least 2-fold for lambda). Since polymerase loading is diminished by 75% before reaching the downstream gamma 1m polyadenylylation site in CESS cells, irrespective of IL-6 induction, transcriptional pausing/termination appears intrinsic and contributes to the selection of gamma 1s and gamma 1m polyadenylylation sites in activated B cells. Furthermore, differential mRNA stabilization is likely to contribute to the alteration of the gamma 1s/gamma 1m mRNA ratio at IL-6 induction.
在选择具有高密度细胞表面IgG1的克隆人B淋巴母细胞系CESS的一个亚群中，研究了白细胞介素6（IL-6）诱导B细胞终末分化的分子机制。用IL-6诱导CESS细胞导致分泌特异性γ1（γ1s）mRNA优先积累15倍，而替代性加工的膜特异性γ1（γ1m）mRNA则没有积累。同样，无生产性重排的μ重链等位基因的微秒mRNA而非微米mRNA也增加。伴随着γ1s mRNA的差异积累，λ轻链mRNA增加了4.5倍，导致IgG1的分泌。对分离细胞核中的转录分析表明，转录激活是免疫球蛋白mRNA定量增加的主要机制（γ1和μ增加5.5倍，λ至少增加2倍）。由于在CESS细胞中，在到达下游γ1m聚腺苷酸化位点之前，聚合酶负载减少了75%，无论是否有IL-6诱导，转录暂停/终止似乎是内在的，并且有助于在活化B细胞中选择γ1s和γ1m聚腺苷酸化位点。此外，差异mRNA稳定性可能有助于在IL-6诱导时改变γ1s/γ1m mRNA比例。
