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.