Abstract
Ileal Crohn's disease (CD) arising from the alteration of intestinal homeostasis is characterized by two features, namely a decrease in Paneth cell-produced antimicrobial peptides that play a key role in maintaining this balance and an increase in NOD2, an intracellular sensor. Although mutations in NOD2 are highly correlated with the incidence of CD, the physiological role of NOD2 in intestinal immunity remains elusive. Here, we show that NOD2 can down-regulate the expression of human enteric antimicrobial peptides during differentiation of the Paneth cell lineage. This finding, which links the decrease of human enteric antimicrobial peptides to increased NOD2 in ileal CD patients, provides a new view into the pathogenesis of ileal CD.
Highlights
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
We show that NOD2 can down-regulate the expression of human enteric antimicrobial peptides during differentiation of the Paneth cell lineage
Consistent with this result, the protein expression of HD5 and HD6 was significantly increased in fibroblast growth factor 9 (FGF9)-stimulated NOD2-siRNAtransfected cells compared with untransfected or mock transfected cells (Fig. 3A and 3B), further confirming that NOD2 signaling can down-regulate the expression of human enteric antimicrobial peptides during differentiation of the Paneth cell lineage; we found no significant differences in the mRNA expression of HD5, HD6, lysozyme and secretory phospholipase A2 (sPLA2) between FGF9-stimulated NOD2-siRNAtransfected cells and NOD2-siRNA transfectants stimulated with FGF9 plus muramyl dipeptide (MDP) (Fig. 2B, 2D, 2F and 2H), suggesting that the down-regulated mRNA expression of human enteric antimicrobial peptides is mediated by MDP via NOD2
Summary
Human Paneth cells serve as a key arm of innate mucosal immunity to maintain the intestinal homeostasis between a host and its colonizing microbes by secreting antimicrobial peptides[7,8]. These antimicrobial peptides are composed predominantly of human enteric a-defensin 5 and 6 (HD5 and HD6) as well as lysozyme and secretory phospholipase A2 (sPLA2), to a lesser extent[9]. Mutations in NOD2 are highly correlated with a diminished expression of human enteric a-defensin[15] and the incidence of CD16,17, the physiological role of NOD2 in intestinal immunity remains elusive. Because Caco[2] intestinal epithelial cells can display characteristics of small intestinal epithelial differentiation in vitro[19,20] and constitutively express the NOD2 gene[13], they are suitable for in vitro studies to investigate the physiological role of NOD2 in specialized intestinal epithelial cells such as Paneth cells
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