Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients.
The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.
Braat
Henri
H
Department of Experimental Internal Medicine, Academic Medical Center, P.O. Box 22700, Meibergdreef 9, 1100 DE Amsterdam, The Netherlands.
Stokkers
Pieter
P
Hommes
Tijmen
T
Cohn
Danny
D
Vogels
Esther
E
Pronk
Inge
I
Spek
Arnold
A
van Kampen
Antoine
A
van Deventer
Sander
S
Peppelenbosch
Maikel
M
Hommes
Daan
D
D000328:Adult; D003424:Crohn Disease / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D011110:Polymorphism, Genetic; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic
D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5