Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis
Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis
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DOI：
10.1073/pnas.1413390111
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发表时间：
2014-09-16
影响因子：
11.1
通讯作者：
Wallace, John L.
中科院分区：
文献类型：
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作者：
Flannigan, Kyle L.;Agbor, Terence A.;Wallace, John L.
维生素B缺乏可导致高同型半胱氨酸血症（Hhcy），在炎症性肠病（IBD）患者中常有报道，并且可能是一个潜在的致病因素。然而，这种作用的机制尚不清楚。硫化氢（H₂S）是一种气体介质，可促进组织修复和炎症消退。在实验性结肠炎中，结肠H₂S合成显著增加可促进溃疡愈合和炎症消退。由于H₂S合成部分依赖于需要维生素B - 6作为辅因子的酶，我们检验了在啮齿动物模型中Hhcy会增加结肠炎易感性这一假设。在所有测试的三种模型中，饮食诱导的Hhcy显著加重了结肠炎。在所有三种结肠炎模型中，结肠炎诱导后结肠H₂S合成通常的升高现象均未出现。给Hhcy大鼠使用H₂S供体可显著降低结肠炎的严重程度。与野生型小鼠相比，正常饮食的白细胞介素（IL）10缺陷型小鼠结肠H₂S合成水平降低，血清同型半胱氨酸增加40%，且表型与患有Hhcy的野生型小鼠相似。喂食维生素B缺乏饮食的IL - 10缺陷型小鼠表现出更严重的结肠炎症，且结肠H₂S合成没有正常升高。给IL - 10缺陷型小鼠使用IL - 10可恢复结肠H₂S合成，并显著降低血清同型半胱氨酸水平。这些结果表明，Hhcy中结肠炎的加重部分是由于结肠H₂S合成受损。此外，IL - 10在促进H₂S产生和同型半胱氨酸代谢方面具有新的作用，这在以Hhcy为特征的疾病中可能具有治疗价值。
Vitamin B deficiencies, which can lead to hyperhomocysteinemia (Hhcy), are commonly reported in patients with inflammatory bowel disease (IBD) and may be a causative underlying factor. However, the mechanism for this effect is not known. Hydrogen sulfide (H2S) is a gaseous mediator that promotes tissue repair and resolution of inflammation. In experimental colitis, a marked increase in colonic H2S synthesis drives ulcer healing and resolution of inflammation. Because H2S synthesis is in part dependent upon enzymes that require vitamin B-6 as a cofactor, we tested the hypothesis that Hhcy in rodent models would increase the susceptibility to colitis. In all three models tested, diet-induced Hhcy significantly exacerbated colitis. The usual elevation of colonic H2S synthesis after induction of colitis was absent in all three models of colitis. Administration of an H2S donor to Hhcy rats significantly decreased the severity of colitis. Compared with wild-type mice, interleukin (IL) 10-deficient mice on a normal diet had decreased levels of colonic H2S synthesis, a 40% increase in serum homocysteine, and a phenotype similar to wild-type mice with Hhcy. IL-10-deficient mice fed the vitamin B-deficient diet exhibited more severe colonic inflammation, but the normal elevation of colonic H2S synthesis was absent. Administration of IL-10 to the IL-10-deficient mice restored colonic H2S synthesis and significantly decreased serum homocysteine levels. These results suggest that the exacerbation of colitis in Hhcy is due in part to impaired colonic H2S synthesis. Moreover, IL-10 plays a novel role in promoting H2S production and homocysteine metabolism, which may have therapeutic value in conditions characterized by Hhcy.