title: Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn's disease is affected by NOD2/CARD15 genotype.
abstract: BACKGROUND
  Blood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptides are inducible after culture with bacterial products and a linkage has been established between them and NOD2/CARD15. The aim was to test whether defensins and cathelicidin (LL-37) expression and NOD2/CARD15 mutations in blood neutrophils are related to molecular bacterial translocation events in CD patients.
  
  
  METHODS
  Fifty consecutively admitted CD patients and 15 healthy controls were included. Clinical and analytical characteristics of patients were considered. NOD2/CARD15 genotyping, presence of bacterial-DNA, defensin and cathelicidin gene, and protein levels in neutrophils and serum cytokine levels were studied.
  
  
  RESULTS
  Twenty patients (40%) presented bacterial-DNA in blood. Eleven were active and 9 were in remission. Bacterial-DNA was not present in controls. NOD2/CARD15 mutations were identified in 25 patients (50%), 15 of which were in remission. Sixty percent of bacterial-DNA(+) and 43% of bacterial-DNA(-) patients showed a NOD2/CARD15 mutation. β-Defensin 2 and LL-37 mRNA and protein levels were upregulated in bacterial-DNA(+) patients. β-Defensin 2 and LL-37 expression correlated with bacterial-DNA concentration only in patients with a wildtype NOD2/CARD15 genotype. Cultured neutrophils of bacterial-DNA(-) patients confirmed the muramyl dipeptide-independent association between DEFB2 and LL-37 with bacterial-DNA concentration in wildtype NOD2/CARD15 patients. Cytokine levels were increased in bacterial-DNA(+) patients and correlated with bacterial-DNA concentration. NOD2/CARD15 genotype did not influence this correlation.
  
  
  CONCLUSIONS
  β-Defensin 2, LL-37, and proinflammatory cytokines are increased in CD patients with bacterial-DNA in a concentration-dependent manner. NOD2/CARD15 plays a key role in the regulation of this response.
authors: Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain.
authors: Ana
authors: A
authors: Gutiérrez
authors: Ernst
authors: E
authors: Holler
authors: Pedro
authors: P
authors: Zapater
authors: Laura
authors: L
authors: Sempere
authors: Rodrigo
authors: R
authors: Jover
authors: Miguel
authors: M
authors: Pérez-Mateo
authors: Juergen
authors: J
authors: Schoelmerich
authors: José
authors: J
authors: Such
authors: Reiner
authors: R
authors: Wiest
authors: Rubén
authors: R
authors: Francés
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003424:Crohn Disease / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D004269:DNA, Bacterial / Q000097:blood / Q000276:immunology*; D005260:Female; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007378:Interleukins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult; D023083:beta-Defensins / Q000097:blood / Q000235:genetics; D054804:Cathelicidins; D000098546:Interleukin-21
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; C106641:DEFB4A protein, human; D004269:DNA, Bacterial; D007378:Interleukins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D007371:Interferon-gamma; D000098546:Interleukin-21; D054804:Cathelicidins