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Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants

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 import...

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Autores principales: Seidelin, Jakob Benedict, Broom, Oliver Jay, Olsen, Jørgen, Nielsen, Ole Haagen
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771351/
https://www.ncbi.nlm.nih.gov/pubmed/19907652
http://dx.doi.org/10.1371/journal.pone.0007794
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author Seidelin, Jakob Benedict
Broom, Oliver Jay
Olsen, Jørgen
Nielsen, Ole Haagen
author_facet Seidelin, Jakob Benedict
Broom, Oliver Jay
Olsen, Jørgen
Nielsen, Ole Haagen
author_sort Seidelin, Jakob Benedict
collection PubMed
description 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 IκB kinase α/β (IKKα/β), the initial step in the nuclear factor κB (NFκB) 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/SIGNIFICANCE: 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.
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spelling pubmed-27713512009-11-12 Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants Seidelin, Jakob Benedict Broom, Oliver Jay Olsen, Jørgen Nielsen, Ole Haagen PLoS One Research Article 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 IκB kinase α/β (IKKα/β), the initial step in the nuclear factor κB (NFκB) 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/SIGNIFICANCE: 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. Public Library of Science 2009-11-12 /pmc/articles/PMC2771351/ /pubmed/19907652 http://dx.doi.org/10.1371/journal.pone.0007794 Text en Seidelin et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Seidelin, Jakob Benedict
Broom, Oliver Jay
Olsen, Jørgen
Nielsen, Ole Haagen
Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title_full Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title_fullStr Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title_full_unstemmed Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title_short Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants
title_sort evidence for impaired card15 signalling in crohn's disease without disease linked variants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771351/
https://www.ncbi.nlm.nih.gov/pubmed/19907652
http://dx.doi.org/10.1371/journal.pone.0007794
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