Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease
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van Heel, DA and Hunt, KA and Ghosh, S and Herve, M and Playford, RJ, Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease, European Journal of Immunology, 36, (6) pp. 1629-1635. ISSN 0014-2980 (2006) [Refereed Article]
Both NOD2/CARD 15 alleles are mutated in ε1 10% of Crohn's disease patients, causing loss of functional responses to low-dose muropeptide agonists. We hypothesized that NOD2 mutations may also impair NOD1/CARD4 responses, supported by data suggesting NOD2 1007fs/1007fs patients had reduced responses to a putative NOD1 agonist, diaminopimelic acid-containing muramyl tripeptide (M-TriDAP). We measured peripheral blood mononuclear cell (n = 8 NOD2 wild type, n = 4 1007fs/1007fs, n = 6 702Trp/1007fs, n = 5 702Trp/702Trp, n = 3 908Arg/1007fs) responses to NOD1 agonists alone (IL-8/TNF-α), and agonist enhancement of lipopolysaccharide (LPS) responses (IL-β). Significant responses were seen with M-TriDAP at 1O nM(aswith NOD2 agonists), but only at ≥100 nM with FK565/TriDAP. M-TriDAP induced IL-8/TNF-α secretion, and enhancement of LPS IL-1β responses was significantly reduced between NOD2 double mutation carriers versus healthy controls, whereas there was no difference with FK565 or TriDAP stimulation, or between 1007fs/1007fs cells and other genotypes. M-TriDAP contains both NOD1 (γ-D-Glu-mesoDAP) and NOD2 (MurNAc-L-Ala-D-Glu) minimal structures whereas FK565/TriDAP contain only NOD1 activating structures. M-TriDAP has dual NOD1/NOD2 agonist activity in primary cells, possibly due to different intracellular peptidoglycan processing compared to the HEK293 cell system typically used for agonist specificity studies. Responses to specific NOD1 agonists are unaffected by NOD2 genotype, suggesting independent action of the NOD1 and NOD2 pathways. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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