Kiss Ildikó, Oskolás Henriett, Tóth Réka, Bouillet Philippe, Tóth Katalin, Fülöp András, Scholtz Beáta, Ledent Catherine, Fésüs László, Szondy Zsuzsa
Department of Biochemistry and Molecular Biology, Signaling and Apoptosis Research Group, Hungarian Academy of Sciences, Research Center of Molecular Medicine, University of Debrecen.
Eur J Immunol. 2006 Jun;36(6):1559-71. doi: 10.1002/eji.200535334.
Adenosine is generated in the microenvironment of emerging thymocytes through normal mechanisms of lymphocyte selection. In a normal thymus, most of the adenosine is catabolized by adenosine deaminase; however, in an environment where up to 95% of the cells undergo programmed cell death, a sufficient amount of adenosine is accumulated to trigger cell surface adenosine receptors. Here we show that accumulated adenosine can induce apoptosis in immature mouse thymocytes, mostly via adenosine A(2A) receptors. The signaling pathway is coupled to adenylate cyclase activation, induction of the Nur77 transcription factor, Nur77-dependent genes, such as Fas ligand and TRAIL, and the pro-apoptotic BH3-only protein Bim. We analyzed several knockout and transgenic mouse lines and found that adenosine-induced killing of mouse thymocytes requires Bim, occurs independently of "death receptor" signaling and is inhibited by Bcl-2 and Nur77. Collectively our data demonstrate that adenosine-induced cell death involves signaling pathways originally found in negative selection of thymocytes and suggest a determining role of Bim and a regulatory role for Nur77.
腺苷通过淋巴细胞选择的正常机制在新生胸腺细胞的微环境中产生。在正常胸腺中，大部分腺苷被腺苷脱氨酶分解代谢；然而，在高达95%的细胞经历程序性细胞死亡的环境中，会积累足够量的腺苷以触发细胞表面腺苷受体。我们在此表明，积累的腺苷可诱导未成熟小鼠胸腺细胞凋亡，主要通过腺苷A(2A)受体。该信号通路与腺苷酸环化酶激活、Nur77转录因子的诱导、Nur77依赖性基因（如Fas配体和TRAIL）以及促凋亡的仅含BH3结构域的蛋白Bim相关。我们分析了几种基因敲除和转基因小鼠品系，发现腺苷诱导的小鼠胸腺细胞杀伤需要Bim，独立于“死亡受体”信号传导发生，且受到Bcl-2和Nur77的抑制。我们的数据共同表明，腺苷诱导的细胞死亡涉及最初在胸腺细胞阴性选择中发现的信号通路，并提示Bim的决定性作用和Nur77的调节作用。
