Flodström M, Chen M C, Smismans A, Schuit F, Pipeleers D G, Eizirik D L
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Cytokine. 1999 Jun;11(6):400-7. doi: 10.1006/cyto.1998.0446.
Nitric oxide (NO) may contribute to pancreatic beta cell damage during the development of type 1 diabetes. Its formation can be triggered by cytokines which induce the expression of the inducible form of nitric oxide synthase (iNOS) in pancreatic islets. In the iNOS-catalyzed reaction, arginine is converted into citrulline and NO. Cellular NO formation may be regulated by the availability of arginine. Arginine can be provided extracellularly, entering the cell mainly through the cationic amino acid transporter system y+CAT, and intracellularly, by protein degradation or synthesis from citrulline (the citrulline-NO cycle). This study demonstrates for the first time that the citrulline-NO cycle is induced in FACS-purified rat beta cells exposed to interleukin-1beta(IL-1beta) and that extracellular arginine or citrulline is required for NO production by beta cells. Moreover, the accumulation of arginine was higher in IL-1beta-treated beta cells than in control cells.beta cells expressed mRNAs for the two y+CAT transporters CAT-2A and CAT-2B with no change in transporter expression after exposure to IL-1beta. It is concluded that the activation of the citrulline-NO cycle and an increase in arginine accumulation may be adaptive responses in cytokine-exposed beta-cells to assure an adequate arginine supply for continuous NO production in the presence of low extracellular arginine levels which may prevail during insulitis.
一氧化氮（NO）可能在1型糖尿病的发展过程中导致胰腺β细胞损伤。其形成可由细胞因子触发，这些细胞因子可诱导胰腺胰岛中诱导型一氧化氮合酶（iNOS）的表达。在iNOS催化的反应中，精氨酸被转化为瓜氨酸和NO。细胞内NO的形成可能受精氨酸可用性的调节。精氨酸可以从细胞外提供，主要通过阳离子氨基酸转运系统y+CAT进入细胞，也可以在细胞内通过蛋白质降解或由瓜氨酸合成（瓜氨酸-NO循环）。本研究首次证明，在暴露于白细胞介素-1β（IL-1β）的经荧光激活细胞分选术（FACS）纯化的大鼠β细胞中，瓜氨酸-NO循环被诱导，并且β细胞产生NO需要细胞外精氨酸或瓜氨酸。此外，经IL-1β处理的β细胞中精氨酸的积累高于对照细胞。β细胞表达两种y+CAT转运体CAT-2A和CAT-2B的mRNA，暴露于IL-1β后转运体表达无变化。得出的结论是，瓜氨酸-NO循环的激活和精氨酸积累的增加可能是细胞因子暴露的β细胞中的适应性反应，以确保在胰岛炎期间可能普遍存在的低细胞外精氨酸水平下有足够的精氨酸供应，用于持续产生NO。
