Graduate School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Biol Pharm Bull. 2012;35(5):805-9. doi: 10.1248/bpb.35.805.
Transcriptional factors of the nuclear factor of activated T cells (NFAT) family are involved in T cell signaling. Many NFAT signaling inhibitors, such as cyclosporin A (CsA) and tacrolimus, abrogate dephosphorylation of NFAT proteins by inhibiting calcineurin activity. In pursuit of a novel type of NFAT signaling inhibitor, we screened our chemical library using the NFAT-dependent reporter assay and identified tributylhexadecylphosphonium bromide (THPB) as a selective NFAT signaling inhibitor. THPB inhibited NFAT-dependent reporter activity, and the induction of interleukin-2 (IL-2) at both mRNA and protein levels by calcium stimulation. Moreover, THPB had an additive effect on the inhibition of IL-2 induction with CsA. Unlike CsA, THPB did not affect dephosphorylation of NFAT1, but suppressed phosphorylation of p70 ribosomal protein S6 kinase (p70S6K). These results suggest that THPB may be a novel type of NFAT signaling inhibitor that acts in association with inhibition of p70S6K phosphorylation.
核因子活化 T 细胞（NFAT）家族的转录因子参与 T 细胞信号转导。许多 NFAT 信号抑制剂，如环孢素 A（CsA）和他克莫司，通过抑制钙调神经磷酸酶活性来阻止 NFAT 蛋白的去磷酸化。为了寻找新型的 NFAT 信号抑制剂，我们使用 NFAT 依赖性报告基因检测法筛选了我们的化学文库，并鉴定出三丁基十六烷基溴化膦（THPB）是一种选择性 NFAT 信号抑制剂。THPB 抑制 NFAT 依赖性报告基因活性，以及钙刺激诱导的白细胞介素 2（IL-2）的 mRNA 和蛋白水平的诱导。此外，THPB 与 CsA 联合使用时对 IL-2 诱导的抑制具有相加作用。与 CsA 不同，THPB 不影响 NFAT1 的去磷酸化，但抑制 p70 核糖体蛋白 S6 激酶（p70S6K）的磷酸化。这些结果表明，THPB 可能是一种新型的 NFAT 信号抑制剂，与抑制 p70S6K 磷酸化有关。
