Deletion of exon I of SMAD7 in mice results in altered B cell responses
Deletion of exon I of SMAD7 in mice results in altered B cell responses
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DOI：
10.4049/jimmunol.176.11.6777
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Heuchel, Rainer L.
中科院分区：
文献类型：
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作者：
Li, Ronggui;Rosendahl, Alexander;Heuchel, Rainer L.
TGF-β超家族的成员，即，TGF-β亚型、激活素和骨形态发生蛋白在胚胎发育和出生后生活期间调节生长、分化和凋亡。Smad 7由TGF-β超家族成员诱导并负性调节其信号传导，因此以负性自分泌反馈方式起作用。此外，Smad 7还受其他刺激诱导。因此，它可以微调和整合TGF-β信号与其他信号通路。为了研究Smad 7在体内的功能作用，我们产生了Smad 7外显子I缺陷的小鼠，导致Smad 7功能的部分丧失。突变动物是可行的，但在远交CD-1小鼠品系背景下显著较小。与野生型小鼠的B细胞相比，突变型B细胞显示出过度活跃的TGF-β信号传导，测量为磷酸化Smad 2阳性B细胞的增加。与预期的TGF-β信号传导增加一致，观察到B细胞应答的几种变化。突变型B细胞表现出增加的IG类转换重组为伊加，显著增强B细胞的自发凋亡，并显著降低对LPS刺激的增殖反应。有趣的是，LPS处理逆转了突变细胞中的凋亡表型。总之，观察到的表型突出了Smad 7在发育和调节免疫系统对TGF-β的反应中的重要作用。
The members of the TGF-beta superfamily, i.e., TGF-beta isoforms, activins, and bone morphogenetic proteins, regulate growth, differentiation, and apoptosis, both during embryonic development and during postnatal life. Smad7 is induced by the TGF-beta superfamily members and negatively modulates their signaling, thus acting in a negative, autocrine feedback manner. In addition, Smad7 is induced by other stimuli. Thus, it can fine-tune and integrate TGF-beta signaling with other signaling pathways. To investigate the functional role(s) of Smad7 in vivo, we generated mice deficient in exon I of Smad7, leading to a partial loss of Smad7 function. Mutant animals are viable, but significantly smaller on the outbred CD-1 mouse strain background. Mutant B cells showed an overactive TGF-beta signaling measured as increase of phosphorylated Smad2-positive B cells compared with B cells from wild-type mice. In agreement with this expected increase in TGF-beta signaling, several changes in B cell responses were observed. Mutant B cells exhibited increased Ig class switch recombination to IgA, significantly enhanced spontaneous apoptosis in B cells, and a markedly reduced proliferative response to LPS stimulation. Interestingly, LPS treatment reverted the apoptotic phenotype in the mutant cells. Taken together, the observed phenotype highlights a prominent role for Smad7 in development and in regulating the immune system's response to TGF-beta.