Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Department of Gastroenterology, the First Affiliated Hospital of South China University, Hengyang 421001, China.
Eur J Cell Biol. 2015 Jan;94(1):60-6. doi: 10.1016/j.ejcb.2014.10.007. Epub 2014 Nov 14.
Human enteric α-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity. Since their expression is decreased in Crohn's disease (CD), with decreased expression being more pronounced in the presence of NOD2 mutations, it would be extremely interesting to investigate the mechanism by which NOD2 may regulate expression of human enteric α-defensins. Here we show that although NOD2 by itself can slightly up-regulate expression of enteric α-defensins mainly through activation of the NF-κB pathway, it can strongly down-regulates their expression during differentiation of the Paneth cell lineage mainly by inhibiting activation of the MAPK pathway. Since NOD2 is over-expressed in CD and mutant NOD2 cannot result in NF-κB activity, our finding can provide an explanation of the previous observation showing decreased expression of human enteric α-defensin in CD and even more so in the presence of NOD2 mutations. In addition, this finding provides a new view on the function of NOD2 in regulating intestinal innate immunity.
人类肠上皮α-防御素（HD5 和 HD6）是肠道潘氏细胞产生的主要抗菌肽，在肠道先天免疫中发挥重要作用。由于其在克罗恩病（CD）中的表达降低，并且在存在 NOD2 突变的情况下表达降低更为明显，因此研究 NOD2 可能调节人类肠上皮α-防御素表达的机制将非常有趣。在这里，我们表明，尽管 NOD2 本身可以通过激活 NF-κB 途径轻微地上调肠上皮α-防御素的表达，但在潘氏细胞谱系的分化过程中，它主要通过抑制 MAPK 途径的激活来强烈地下调其表达。由于 NOD2 在 CD 中过度表达，并且突变型 NOD2 不能导致 NF-κB 活性，我们的发现可以解释先前观察到的 CD 中人类肠上皮α-防御素表达降低的现象，在存在 NOD2 突变的情况下更为明显。此外，这一发现为 NOD2 在调节肠道先天免疫中的功能提供了一个新的视角。
