Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation.
The nucleotide oligomerization domain 2 (NOD2) 3020insC (NOD2fs) mutation increases susceptibility to Crohn's disease (CD), but the mechanism remains controversial. Loss-of-function and gain-of-function phenotypes have been described as a result of NOD2fs. Here, we show that dendritic cells (DC) derived from CD patients homozygous for this mutation respond normally to purified Toll-like receptor (TLR) ligands but fail to up-regulate the costimulatory molecules CD80 and CD86 in response to the NOD2 ligand muramyl dipeptide (MDP). Moreover, they lack MDP-induced enhancement of TLR-mediated tumor necrosis factor alpha, interleukin (IL)-12, and IL-10 production, which is observed in control DC with intact NOD2. These data indicate that the NOD2fs mutation results in a loss-of-function phenotype in human myeloid DC and imply decreased immune regulation by IL-10 as a possible mechanism for this mutation in CD.
Kramer
Matthijs
M
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Netea
Mihai G
MG
de Jong
Dirk J
DJ
Kullberg
Bart Jan
BJ
Adema
Gosse J
GJ
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000328:Adult; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D051193:Toll-Like Receptors / Q000276:immunology
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine