Muramyl dipeptide-induced differential gene expression in NOD2 mutant and wild-type Crohn's disease patient-derived dendritic cells.
BACKGROUND
Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completely understood. To study the mechanism of CD resulting from NOD2 mutations, we analyzed NOD2-dependent whole-genome expression profiles of patient-derived antigen-presenting cells.


METHODS
Monocyte-derived dendritic cells (DCs) from CD carriers of double-dose NOD2 mutations, wild-type CD patients, and wild-type healthy volunteers were stimulated with the NOD2 ligand muramyl dipeptide. Whole-genome microarrays were used to assess the differential gene expression. The clustering of significantly changed genes was analyzed by online gene ontology mapping software.


RESULTS
In the DCs from the wild-type CD patient group, 683 genes were significantly changed, with most of the genes clustering in the pathways of inflammatory response. In addition, a significant number of genes clustered in the apoptosis regulation-related pathway. In the DCs from the healthy volunteer group, only 50 genes were significantly changed, predominantly those belonging to the response to pathogen pathway. Analysis of differentially expressed gene ontology pathways in the DCs from the NOD2 mutant CD patient group showed that the transcription of pathogen response genes was absent. In this group, 298 genes were significantly changed, predominantly clustering in the negative apoptosis regulation and cell organization and biogenesis pathways.


CONCLUSIONS
Our results suggest that NOD2 mutations may result in perpetuation of mucosal inflammation through insufficient pathogen elimination. Further, these observations implicate a possible role of defective regulation of dendritic cell apoptosis in CD pathogenesis.
Zelinkova
Zuzana
Z
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. z.zelinkova@amc.uva.nl
van Beelen
Astrid J
AJ
de Kort
Floor
F
Moerland
Perry D
PD
Ver Loren van Themaat
Emiel
E
te Velde
Anje A
AA
van Deventer
Sander J
SJ
de Jong
Esther C
EC
Hommes
Daniel W
DW
D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000276:Adjuvants, Immunologic; D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis
D000276:Adjuvants, Immunologic; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine