title: Evidence for impaired CARD15 signalling in Crohn's disease without disease linked variants.
abstract: BACKGROUND
  Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants.
  
  
  RESULTS
  By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes.
  
  
  CONCLUSIONS
  These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing.
authors.affiliation: Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark. jseidelin@dadlnet.dk
authors.forename: Jakob Benedict
authors.initials: JB
authors.lastname: Seidelin
authors.forename: Oliver Jay
authors.initials: OJ
authors.lastname: Broom
authors.forename: Jørgen
authors.initials: J
authors.lastname: Olsen
authors.forename: Ole Haagen
authors.initials: OH
authors.lastname: Nielsen
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005091:Exons; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D000119:Acetylmuramyl-Alanyl-Isoglutamine