Martin Florent, Penet Marie-France, Malergue Fabrice, Lepidi Hubert, Dessein Alain, Galland Franck, de Reggi Max, Naquet Philippe, Gharib Bouchra
Centre d'Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale, Universté de la Méditerranée, Marseille, France.
J Clin Invest. 2004 Feb;113(4):591-7. doi: 10.1172/JCI19557.
Vanin-1 is a membrane-anchored pantetheinase highly expressed in the gut and liver. It hydrolyzes pantetheine to pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine. The latter is believed to be a key regulating factor of several essential metabolic pathways, acting through sulfhydryl-disulfide exchange reactions between sulfhydryl groups of the enzymes and the oxidized form, cystamine. Its physiological importance remains to be elucidated, however. To explore this point, we developed Vanin-1-deficient mice that lack free cysteamine. We examined the susceptibility of deficient mice to intestinal inflammation, either acute (NSAID administration) or chronic (Schistosoma infection). We found that Vanin-1(-/-) mice better controlled inflammatory reaction and intestinal injury in both experiments. This protection was associated with increased gamma-glutamylcysteine synthetase activity and increased stores of reduced glutathione, as well as reduced inflammatory cell activation in inflamed tissues. Oral administration of cystamine reversed all aspects of the deficient phenotype. These findings suggest that one cysteamine function is to upregulate inflammation. Consequently, the pantetheinase activity of Vanin-1 molecule could be a target for a new anti-inflammatory strategy.
泛酰巯基乙胺酶-1是一种膜锚定的泛酰巯基乙胺酶，在肠道和肝脏中高度表达。它将泛酰巯基乙胺水解为泛酸（维生素B5）和低分子量硫醇半胱胺。后者被认为是几种重要代谢途径的关键调节因子，通过酶的巯基与氧化形式胱胺之间的巯基-二硫键交换反应发挥作用。然而，其生理重要性仍有待阐明。为了探究这一点，我们培育了缺乏游离半胱胺的泛酰巯基乙胺酶-1缺陷小鼠。我们研究了缺陷小鼠对急性（给予非甾体抗炎药）或慢性（感染血吸虫）肠道炎症的易感性。我们发现，在这两个实验中，泛酰巯基乙胺酶-1（-/-）小鼠能更好地控制炎症反应和肠道损伤。这种保护作用与γ-谷氨酰半胱氨酸合成酶活性增加、还原型谷胱甘肽储备增加以及炎症组织中炎症细胞活化减少有关。口服胱胺可逆转缺陷表型的所有方面。这些发现表明，半胱胺的一个功能是上调炎症反应。因此，泛酰巯基乙胺酶-1分子的泛酰巯基乙胺酶活性可能是一种新的抗炎策略的靶点。
