Ahuja S S, Paliogianni F, Yamada H, Balow J E, Boumpas D T
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1993 Apr 15;150(8 Pt 1):3109-18.
Transforming growth factors-beta (TGF-beta) modulate immune responses by inhibiting the proliferation of normal T lymphocytes. To examine the mechanism(s) of this inhibition, we studied the effect of TGF-beta 1 on selected events associated with the initiation and progression of the T lymphocyte cell cycle. Human peripheral blood T cells were stimulated with anti-CD3 mAb, PHA, PMA, or ionomycin, alone or in combination. TGF-beta 1 (0.5 to 10 ng/ml) partially inhibited the tyrosine phosphorylation of a 100-kDa protein, but not the calcium influx when cells were stimulated via TCR. Nuclear transcription of early activation genes (c-fos, c-jun, and c-myc) as determined by nuclear run-off assays, and steady state mRNA levels and/or protein products of intermediate activation genes (IL-2, IL-2R alpha, IL-2R beta, and transferrin receptor) were not affected by TGF-beta 1. Total cellular RNA synthesis and cell size after T cell stimulation were also not affected by TGF-beta 1. However, TGF-beta 1 inhibited the IL-2-dependent proliferation of Con A lymphoblasts by -50%. This inhibition was associated with the down-regulation of IL-2-mediated tyrosine phosphorylation of proteins of 120, 100, 85, 75, and 50 kDa. TGF-beta 1 also inhibited the IL-2-dependent phosphorylation of the retinoblastoma susceptibility gene product, which plays an important role in cell cycle progression. These results suggest that TGF-beta 1 inhibits T cell proliferation by down-regulating predominantly IL-2-mediated proliferative signals.
转化生长因子-β（TGF-β）通过抑制正常T淋巴细胞的增殖来调节免疫反应。为了研究这种抑制作用的机制，我们研究了TGF-β1对与T淋巴细胞细胞周期启动和进展相关的特定事件的影响。用人外周血T细胞单独或联合抗CD3单克隆抗体、PHA、PMA或离子霉素进行刺激。当细胞通过TCR受到刺激时，TGF-β1（0.5至10 ng/ml）部分抑制了一种100 kDa蛋白的酪氨酸磷酸化，但不抑制钙内流。通过核转录分析确定的早期激活基因（c-fos、c-jun和c-myc）的核转录，以及中间激活基因（IL-2、IL-2Rα、IL-2Rβ和转铁蛋白受体）的稳态mRNA水平和/或蛋白质产物不受TGF-β1的影响。T细胞刺激后的总细胞RNA合成和细胞大小也不受TGF-β1的影响。然而，TGF-β1抑制了伴刀豆球蛋白A淋巴母细胞依赖IL-2的增殖达50%。这种抑制与IL-2介导的120、100、85、75和50 kDa蛋白酪氨酸磷酸化的下调有关。TGF-β1还抑制了视网膜母细胞瘤易感基因产物的IL-2依赖性磷酸化，该基因产物在细胞周期进程中起重要作用。这些结果表明，TGF-β1主要通过下调IL-2介导的增殖信号来抑制T细胞增殖。
