Zelazowski P, Carrasco D, Rosas F R, Moorman M A, Bravo R, Snapper C M
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
J Immunol. 1997 Oct 1;159(7):3133-9.
The Ig heavy chain locus contains a number of binding sites for the transcriptional activator, c-Rel. In this study, we evaluated the capacity of B cells from mice made genetically deficient in the C-terminal, transactivation domain of the c-Rel protein (delta c-Rel) to undergo Ig class switching. Flow-cytometric and digestion circularization PCR analyses revealed that delta c-Rel B cells failed to switch to IgG3 in response to LPS alone, or to IgG1 or IgE in response to LPS + IL-4. This failure to switch to IgG3 or IgG1 was associated with a corresponding loss of germline CH gamma 3 or CH gamma 1 RNA. However, the defective switching to IgE in delta c-Rel B cells was associated with normal levels of germline CH epsilon RNA relative to control B cells. The ability of delta c-Rel B cells to switch to IgG1, in response to LPS + IL-4, could be restored through the action(s) of additional stimuli, and this was associated with induction of normal levels of germline CH gamma 1 RNA relative to controls. In contrast, LPS-activated B cells from delta c-Rel mice underwent normal switching to IgA in the presence of TGF-beta, relative to control B cells. This was associated with equivalent steady state levels of germline CH alpha RNA between the two B cell populations. These data are the first to demonstrate a key and selective role for c-Rel in the regulation of Ig class switching. Furthermore, distinct differences are revealed in the Ig isotype induction profiles of B cells lacking c-Rel activity vs those deficient in p50/nuclear factor-kappa B.
免疫球蛋白重链基因座包含多个转录激活因子c-Rel的结合位点。在本研究中，我们评估了c-Rel蛋白C端反式激活结构域基因缺失小鼠（δc-Rel）的B细胞进行免疫球蛋白类别转换的能力。流式细胞术和消化环化PCR分析显示，δc-Rel B细胞单独对脂多糖（LPS）无反应，不能转换为IgG3；对LPS +白细胞介素-4（IL-4）也无反应，不能转换为IgG1或IgE。不能转换为IgG3或IgG1与种系CHγ3或CHγ1 RNA相应缺失有关。然而，δc-Rel B细胞向IgE转换缺陷与相对于对照B细胞种系CHεRNA水平正常有关。δc-Rel B细胞对LPS + IL-4反应转换为IgG1的能力可通过其他刺激作用恢复，这与相对于对照诱导正常水平的种系CHγ1 RNA有关。相比之下，相对于对照B细胞，来自δc-Rel小鼠的LPS激活B细胞在转化生长因子-β（TGF-β）存在下正常转换为IgA。这与两个B细胞群体之间种系CHαRNA的等效稳态水平有关。这些数据首次证明c-Rel在免疫球蛋白类别转换调节中起关键和选择性作用。此外，还揭示了缺乏c-Rel活性的B细胞与缺乏p50/核因子-κB的B细胞在免疫球蛋白同种型诱导谱上的明显差异。
