Synergistic enhancement of Toll-like receptor responses by NOD1 activation.
NOD1 is an intracellular pattern-recognition receptor specific for Gram-negative peptidoglycan that is important in host response to infections (e.g. Helicobacter pylori and Shigella flexneri). Genetic variation in NOD1 predisposes to asthma and inflammatory bowel disease. Functional responses have not previously been studied in primary human cells. NOD1 activation by low nanomolar concentrations of the specific muropeptide ligand M-TriDAP induced minimal human peripheral blood mononuclear cell TNF-alpha, IL-1beta or IL-10 secretion, but synergistically increased Toll-like receptor (TLR)-induced responses. Synergistic responses were seen across multiple ligands (to TLR1/2, 2/6, 4, 5, 7/8) and a broad range of cytokine secretion (TNF-alpha, IL-1alpha, IL-1beta, IL-4, IL-6, IL-10, GM-CSF). Synergy was also observed in the allogeneic mixed lymphocyte reaction. These responses were similar in cells homozygous for Crohn's disease-associated NOD2 mutations. In contrast to cell lines, primary human peripheral blood mononuclear cells respond to NOD1 muropeptides at approximately 100-fold lower concentrations. Cross-talk between cytosolic NOD1 and membrane-bound TLR enhances responses to the multiple antigens simultaneously presented by a microbe.
van Heel
David A
DA
Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London Hammersmith Campus, London, UK. d.vanheel@imperial.ac.uk
Ghosh
Subrata
S
Butler
Matt
M
Hunt
Karen
K
Foxwell
Brian Michael J
BM
Mengin-Lecreulx
Dominique
D
Playford
Raymond J
RJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism* / Q000502:physiology; D000276:Adjuvants, Immunologic / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D051194:Toll-Like Receptor 1; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; D051194:Toll-Like Receptor 1; D051193:Toll-Like Receptors