Document Detail


NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes.
MedLine Citation:
PMID:  18383179     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Inflammatory bowel diseases     Volume:  14     ISSN:  1536-4844     ISO Abbreviation:  Inflamm. Bowel Dis.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-07-17     Completed Date:  2008-11-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9508162     Medline TA:  Inflamm Bowel Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1033-40     Citation Subset:  IM    
Affiliation:
Department of Surgery, Innenstadt, University of Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Acetylmuramyl-Alanyl-Isoglutamine / 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:
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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