Kokkotou E, Espinoza D O, Torres D, Karagiannides I, Kosteletos S, Savidge T, O'Brien M, Pothoulakis C
Division of Gastroenterology, Dana 501, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Gut. 2009 Jan;58(1):34-40. doi: 10.1136/gut.2008.155341. Epub 2008 Sep 29.
Melanin-concentrating hormone (MCH) is a hypothalamic orexigenic neuropeptide that regulates energy balance. However, the distribution of MCH and its receptor MCHR1 in tissues other than brain suggested additional, as yet unappreciated, roles for this neuropeptide. Based on previous paradigms and the presence of MCH in the intestine as well as in immune cells, its potential role in gut innate immune responses was examined.
In human intestinal xenografts grown in mice, changes in the expression of MCH and its receptors following treatment with Clostridium difficile toxin A, the causative agent of antibiotic-associated diarrhoea in hospitalised patients, were examined. In colonocytes, the effect of C difficile toxin A treatment on MCHR1 expression, and of MCH on interleukin 8 (IL8) expression was examined. MCH-deficient mice and immunoneutralisation approaches were used to examine the role of MCH in the pathogenesis of C difficile toxin A-mediated acute enteritis.
Upregulation of MCH and MCHR1 expression was found in the human intestinal xenograft model, and of MCHR1 in colonocytes following exposure to toxin A. Treatment of colonocytes with MCH resulted in IL8 transcriptional upregulation, implying a link between MCH and inflammatory pathways. In further support of this view, MCH-deficient mice developed attenuated toxin A-mediated intestinal inflammation and secretion, as did wild-type mice treated with an antibody against MCH or MCHR1.
These findings signify MCH as a mediator of C difficile-associated enteritis and possibly of additional gut pathogens. MCH may mediate its proinflammatory effects at least in part by acting on epithelial cells in the intestine.
黑色素浓缩激素（MCH）是一种下丘脑促食欲神经肽，可调节能量平衡。然而，MCH及其受体MCHR1在脑以外组织中的分布提示该神经肽可能具有其他尚未被认识的作用。基于以往的研究模式以及肠道和免疫细胞中存在MCH，研究了其在肠道固有免疫反应中的潜在作用。
在小鼠体内生长的人肠道异种移植模型中，检测了用艰难梭菌毒素A（住院患者抗生素相关性腹泻的病原体）处理后MCH及其受体表达的变化。在结肠细胞中，检测了艰难梭菌毒素A处理对MCHR1表达的影响以及MCH对白细胞介素8（IL8）表达的影响。使用MCH缺陷小鼠和免疫中和方法研究MCH在艰难梭菌毒素A介导的急性肠炎发病机制中的作用。
在人肠道异种移植模型中发现MCH和MCHR1表达上调，在暴露于毒素A后的结肠细胞中MCHR1表达上调。用MCH处理结肠细胞导致IL8转录上调，这意味着MCH与炎症途径之间存在联系。进一步支持这一观点的是，MCH缺陷小鼠毒素A介导的肠道炎症和分泌减弱，用抗MCH或MCHR1抗体处理的野生型小鼠也是如此。
这些发现表明MCH是艰难梭菌相关性肠炎以及可能其他肠道病原体的介质。MCH可能至少部分通过作用于肠道上皮细胞来介导其促炎作用。
