Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease
| Autor: | Mireille Hervé, David A. van Heel, Subrata Ghosh, Karen A. Hunt, Raymond J. Playford |
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| Rok vydání: | 2006 |
| Předmět: |
Agonist
Lipopolysaccharides medicine.medical_specialty Lipopolysaccharide Genotype medicine.drug_class Immunology Nod2 Signaling Adaptor Protein Stimulation Enzyme-Linked Immunosorbent Assay Peptidoglycan Biology Peripheral blood mononuclear cell Frameshift mutation chemistry.chemical_compound Crohn Disease Internal medicine NOD2 Nod1 Signaling Adaptor Protein medicine Immunology and Allergy Humans Adaptor Proteins Signal Transducing Tumor Necrosis Factor-alpha Interleukin-8 Wild type Intracellular Signaling Peptides and Proteins digestive system diseases body regions Endocrinology chemistry Acetylmuramyl-Alanyl-Isoglutamine Interleukin-1 |
| Zdroj: | European journal of immunology. 36(6) |
| ISSN: | 0014-2980 |
| Popis: | Both NOD2/CARD15 alleles are mutated in approximately 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-alpha), and agonist enhancement of lipopolysaccharide (LPS) responses (IL-1beta). Significant responses were seen with M-TriDAP at 10 nM (as with NOD2 agonists), but only at > or =100 nM with FK565/TriDAP. M-TriDAP induced IL-8/TNF-alpha secretion, and enhancement of LPS IL-1beta 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 (gamma-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. |
| Databáze: | OpenAIRE |
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