Department of Biochemistry and Molecular Biology, Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Research Center of Molecular Medicine, University Medical School of Debrecen, Nagyerdei krt. 98, Debrecen 4012, Hungary.
Amino Acids. 2013 Jan;44(1):235-44. doi: 10.1007/s00726-011-1119-4. Epub 2011 Oct 14.
Transglutaminase 2 (TG2) has been known for a long time to be associated with the in vivo apoptosis program of various cell types including T cells. Though the expression of the enzyme was strongly induced in mouse thymocytes following apoptosis induction in vivo, no significant induction of TG2 could be detected, when thymocytes were induced to die by the same stimuli in vitro indicating that signals arriving from the tissue environment are required for the in vivo induction of the enzyme in apoptotic thymocytes. Previous studies have shown that one of these signals is transforming growth factor-β (TGF-β) which is released by macrophages engulfing apoptotic cells. Besides TGF-β, the TG2 promoter contains retinoic acid response elements as well. Here we show that in vitro retinoic acids, or TGF-β and retinoic acids together can significantly enhance the TG2 mRNA expression in dying thymocytes, and the apoptotic signal contributes to the TG2 induction. Inhibition of retinoic acid synthesis either by alcohol or retinaldehyde dehydrogenases significantly attenuates the in vivo induction of TG2 following apoptosis induction indicating that retinoids indeed might contribute in vivo to the apoptosis-related TG2 expression. What is more, the in vivo apoptosis induction in the thymus is accompanied by an enhanced retinoid-dependent transcriptional activity due to the enhanced retinoid synthesis by macrophages engulfing apoptotic cells. Our data reveal a new crosstalk between macrophages and apoptotic cells, in which apoptotic cell uptake-induced retinoid synthesis in macrophages enhances TG2 expression in the dying thymocytes.
转谷氨酰胺酶 2（TG2）长期以来一直与包括 T 细胞在内的各种细胞类型的体内细胞凋亡程序有关。尽管在体内诱导凋亡后，小鼠胸腺细胞中 TG2 的表达强烈诱导，但在体外通过相同刺激诱导胸腺细胞死亡时，并未检测到 TG2 的明显诱导，这表明需要来自组织环境的信号来诱导凋亡胸腺细胞中酶的体内诱导。先前的研究表明，这些信号之一是转化生长因子-β（TGF-β），它是吞噬凋亡细胞的巨噬细胞释放的。除了 TGF-β，TG2 启动子还包含视黄酸反应元件。在这里，我们表明，在体外视黄酸或 TGF-β和视黄酸一起可以显著增强凋亡胸腺细胞中 TG2 mRNA 的表达，并且凋亡信号有助于 TG2 的诱导。通过酒精或视黄醛脱氢酶抑制视黄酸合成会显著减弱凋亡诱导后 TG2 的体内诱导，表明视黄酸确实可能在体内有助于与凋亡相关的 TG2 表达。更重要的是，由于吞噬凋亡细胞的巨噬细胞增强了视黄酸的合成，胸腺中的体内凋亡诱导伴随着增强的依赖视黄酸的转录活性。我们的数据揭示了巨噬细胞和凋亡细胞之间的新串扰，其中凋亡细胞摄取诱导的巨噬细胞中的视黄酸合成增强了垂死胸腺细胞中的 TG2 表达。
