Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg Sweden.
Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Immunol Lett. 2018 Jun;198:7-11. doi: 10.1016/j.imlet.2018.03.014. Epub 2018 Mar 29.
The transcription factor DEC1/STRA13 (also known as BHLHE40 and SHARP2) is involved in a number of processes including inhibition of cell proliferation and delay of cell cycle, and is a negative regulator of B cell activation and development in mice. We show here that, unlike in mice, DEC1/STRA13 expression is induced in human naïve and memory resting B cells by activation through the B-cell receptor (BCR) or Toll-like receptor 9 (TLR9). siRNA silencing of DEC1/STRA13 increases the capacity of activated B cells to perform a high number of divisions after TLR9 ligation. This identifies DEC1/STRA13 as a critical negative regulator of clonal expansion of activated human B cells. We also show that DEC1/STRA13 is upregulated in human anergic CD21 B cells clonally expanded in patients with HCV-associated mixed cryoglobulinemia, which fail to proliferate in response to BCR or TLR9 ligation. siRNA knockdown of DEC1/STRA13, however, fails to restore responsiveness to stimuli in these cells, although it might improve the proliferative capacity in a subset of anergic cells with less pronounced proliferative defect.
转录因子 DEC1/STRA13（也称为 BHLHE40 和 SHARP2）参与多种过程，包括抑制细胞增殖和细胞周期延迟，并且是小鼠 B 细胞激活和发育的负调节剂。我们在这里表明，与在小鼠中不同，DEC1/STRA13 的表达在人类幼稚和记忆静止 B 细胞中通过 B 细胞受体（BCR）或 Toll 样受体 9（TLR9）的激活而被诱导。DEC1/STRA13 的 siRNA 沉默增加了激活的 B 细胞在 TLR9 连接后进行大量分裂的能力。这表明 DEC1/STRA13 是激活的人类 B 细胞克隆扩增的关键负调节剂。我们还表明，在 HCV 相关混合性冷球蛋白血症患者中克隆扩增的人无反应性 CD21 B 细胞中 DEC1/STRA13 上调，这些细胞对 BCR 或 TLR9 连接无反应性。然而，siRNA 敲低 DEC1/STRA13 并不能恢复这些细胞对刺激的反应性，尽管它可能会改善具有不太明显增殖缺陷的无反应性细胞亚群的增殖能力。
