Li Ronggui, Rosendahl Alexander, Brodin Greger, Cheng Alec M, Ahgren Aive, Sundquist Christina, Kulkarni Sarang, Pawson Tony, Heldin Carl-Henrik, Heuchel Rainer L
Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
J Immunol. 2006 Jun 1;176(11):6777-84. doi: 10.4049/jimmunol.176.11.6777.
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.
转化生长因子-β（TGF-β）超家族成员，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中均调节生长、分化和细胞凋亡。Smad7由TGF-β超家族成员诱导产生，并对其信号传导起负调节作用，从而以负性自分泌反馈方式发挥作用。此外，Smad7还可由其他刺激诱导产生。因此，它能够对TGF-β信号传导与其他信号通路进行微调并整合。为了研究Smad7在体内的功能作用，我们构建了Smad7外显子I缺失的小鼠，导致Smad7功能部分丧失。突变动物能够存活，但在远交系CD-1小鼠品系背景下体型明显较小。与野生型小鼠的B细胞相比，突变型B细胞中磷酸化Smad2阳性B细胞增加，提示TGF-β信号传导过度活跃。与TGF-β信号传导预期增加相一致，观察到B细胞反应有若干变化。突变型B细胞向IgA的Ig类别转换重组增加，B细胞中的自发凋亡显著增强，对LPS刺激的增殖反应明显降低。有趣的是，LPS处理可使突变细胞中的凋亡表型恢复。综上所述，观察到的表型突出了Smad7在发育以及调节免疫系统对TGF-β反应中的重要作用。
