| NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes. | |
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MedLine Citation:
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PMID: 18383179 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: The functional link between mutations in NOD2 and Crohn's disease (CD) has not been entirely elucidated. The 1007fs mutation results in loss of NF-kappaB activation in response to muramyl dipeptide (MDP) but has also been linked to an increased IL-1beta processing and IL-12 release. METHODS: We investigated the basal and MDP-triggered mRNA expression and protein release for TNF-alpha, IL-10, IL-1beta, and IL-12p40 in peripheral blood monocytes from 40 CD patients and 15 healthy individuals with different NOD2 genotypes. RESULTS: Monocytes from individuals with 2 mutated NOD2 alleles (homozygous and compound-heterozygous individuals) displayed an impaired release of TNF-alpha and IL-10 but also of IL-1beta and IL-12p40 in response to MDP. In contrast to other NOD2 variants, the presence of at least 1 1007fs allele in double-mutated individuals completely abrogated NOD2 receptor function. Interestingly, monocytes from CD patients with 2 mutated NOD2 alleles displayed significantly higher basal levels of IL-12p40 in cell culture supernatants compared to wildtype CD patients and control individuals (P = 0.002 and P = 0.008, respectively). This was regardless of the IL23R genotype and was not mirrored by increased IL-12p40 plasma levels in these individuals. CONCLUSIONS: The CD-associated NOD2 variants lead, in a dose- and mutation-dependent manner, to an impaired release of TNF-alpha, IL-10, IL-1beta, and IL-12p40 in response to MDP. The finding of increased basal levels for IL-12p40-related cytokines in monocytes with 2 mutated NOD2 alleles is likely to set a new link between NOD2 mutations and the inflammatory mechanisms underlying CD. |
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Authors:
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Vanessa Beynon; Sebastian Cotofana; Stephan Brand; Peter Lohse; Anja Mair; Stefanie Wagner; Thomas Mussack; Thomas Ochsenkühn; Matthias Folwaczny; Christian Folwaczny; Jürgen Glas; Helga-Paula Török |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Inflammatory bowel diseases Volume: 14 ISSN: 1536-4844 ISO Abbreviation: Inflamm. Bowel Dis. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-17 Completed Date: 2008-11-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9508162 Medline TA: Inflamm Bowel Dis Country: United States |
Other Details:
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Languages: eng Pagination: 1033-40 Citation Subset: IM |
Affiliation:
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Department of Surgery, Innenstadt, University of Munich, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylmuramyl-Alanyl-Isoglutamine
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pharmacology Adjuvants, Immunologic / pharmacology* Case-Control Studies Crohn Disease / genetics* Dose-Response Relationship, Drug Female Genotype Humans Interleukin-10 / metabolism Interleukin-12 Subunit p40 / metabolism* Interleukin-1beta / metabolism Male Monocytes / drug effects, metabolism* Nod2 Signaling Adaptor Protein / genetics* Tumor Necrosis Factor-alpha |
| Chemical | |
Reg. No./Substance:
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0/Adjuvants, Immunologic; 0/Interleukin-12 Subunit p40; 0/Interleukin-1beta; 0/NOD2 protein, human; 0/Nod2 Signaling Adaptor Protein; 0/Tumor Necrosis Factor-alpha; 130068-27-8/Interleukin-10; 53678-77-6/Acetylmuramyl-Alanyl-Isoglutamine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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