NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes
✍ Scribed by 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
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 209 KB
- Volume
- 14
- Category
- Article
- ISSN
- 1078-0998
No coin nor oath required. For personal study only.
✦ Synopsis
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-B activation in response to muramyl dipeptide (MDP) but has also been linked to an increased IL-1 processing and IL-12 release.
Methods:
We investigated the basal and MDP-triggered mRNA expression and protein release for TNF-␣, IL-10, IL-1, 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-␣ and IL-10 but also of IL-1 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 ϭ 0.002 and P ϭ 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 doseand mutation-dependent manner, to an impaired release of TNF-␣, IL-10, IL-1, 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.