Tsuzaka Kensei, Fukuhara Izumi, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu
Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, Kamoda 1981, Kawagoe, Saitama 350-8550, Japan.
J Immunol. 2003 Sep 1;171(5):2496-503. doi: 10.4049/jimmunol.171.5.2496.
The reduction or absence of TCR zeta-chain (zeta) expression in systemic lupus erythematosus (SLE) patients is thought to be related to the pathogenesis of SLE. Recently, we reported the predominant expression of zeta mRNA containing an alternatively spliced 3'-untranslated region (3'UTR; zetamRNA/as-3'UTR) and a reduction in the expression of zeta mRNA containing the wild-type 3'UTR (zetamRNA/w-3'UTR) in T cells from SLE patients. Here we show that AS3'UTR mutants (MA5.8 cells deficient in zeta protein that have been transfected with zetamRNA/as-3'UTR) exhibit a reduction in the expression of TCR/CD3 complex and zeta protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab compared with that in wild-type 3'UTR mutants (MA5.8 cells transfected with zetamRNA/w-3'UTR). Furthermore, the real-time PCR analyses demonstrated that the half-life of zetamRNA/as-3'UTR in AS3'UTR mutants (3 h) was much shorter than that of zetamRNA/w-3'UTR in wild-type 3'UTR mutants (15 h). Thus, the lower stability of zetamRNA/as-3'UTR, which is predominant in SLE T cells, may be responsible for the reduced expression of the TCR/CD3 complex, including zeta protein, in SLE T cells.
系统性红斑狼疮（SLE）患者中TCR ζ链（ζ）表达的减少或缺失被认为与SLE的发病机制有关。最近，我们报道了在SLE患者的T细胞中，含有可变剪接3'非翻译区（3'UTR；ζmRNA/as-3'UTR）的ζmRNA占主导表达，而含有野生型3'UTR（ζmRNA/w-3'UTR）的ζmRNA表达减少。在此我们表明，与野生型3'UTR突变体（转染了ζmRNA/w-3'UTR的MA5.8细胞）相比，AS3'UTR突变体（转染了ζmRNA/as-3'UTR且ζ蛋白缺陷的MA5.8细胞）在抗CD3抗体刺激后，其细胞表面TCR/CD3复合物和ζ蛋白的表达减少，IL-2的产生也减少。此外，实时PCR分析表明，AS3'UTR突变体中ζmRNA/as-3'UTR的半衰期（3小时）比野生型3'UTR突变体中ζmRNA/w-3'UTR的半衰期（15小时）短得多。因此，在SLE T细胞中占主导的ζmRNA/as-3'UTR较低的稳定性，可能是SLE T细胞中包括ζ蛋白在内的TCR/CD3复合物表达减少的原因。
