MDP-Induced selective tolerance to TLR4 ligands: impairment in NOD2 mutant Crohn's disease patients.
BACKGROUND
Pathogen infection is a complex process in which several pathogen-recognition receptor (PRR) pathways are activated to induce proinflammatory mediators. The activation of multiple PRRs suggests an interaction between Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptor (NOD) signaling pathways.


METHODS
To understand the modulation induced by NOD2 signals on successive responses to pathogen-associated molecular patterns (PAMPs), we examined how muramyl dipeptide (MDP) pretreatment reprograms the MDP+LPS (lipopolysaccharide) response of monocytes from human peripheral blood.


RESULTS
Preexposure to bacterial MDP components induced selective tolerance to a subsequent NOD2+TLR4 stimulation. MDP pretreatment inhibited the production of tumor necrosis factor alpha (TNFalpha) and interleuken 10 (IL10), whereas IL6 and IL8 remained unaffected. MDP-induced tolerance was independent of receptor downregulation but was associated with reduced levels of phosphorylated TAK1 and abrogated phosphorylation of the downstream MAPK.Since Nod2 mutations have been associated with susceptibility to develop Crohn's disease (CD), we compared the MDP-induced tolerance in healthy donors and CD patients with compound heterozygous Nod2 mutations (Mut-Nod2) expressing variant NOD2 proteins. MDP-induced tolerance in Mut-Nod2 patients reduced IL10 but not TNFalpha production. In contrast with healthy donors, a p38-independent TNFalpha production was observed during the kinetics of the MDP+LPS response in Mut-Nod2 patients.


CONCLUSIONS
Our findings suggest that the selective tolerance induced by MDP in healthy donors was related to the modulation of a convergent nub of NOD2 and TLR4 signaling pathways. This MDP-induced tolerance was impaired in Mut-Nod2 CD patients, resulting in a p38-independent TNFalpha production and an imbalance between pro- and antiinflammatory cytokines that could be partly responsible for the pathogenesis of CD.
Cantó
Elisabet
E
Department of Immunology, Institut Rec & Hospital Sant Pau, Barcelona, Spain.
Moga
Esther
E
Ricart
Elena
E
Garcia-Bosch
Orlando
O
Garcia-Planella
Esther
E
Juarez
Candido
C
Vidal
Silvia
S
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016130:Immunophenotyping; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000276:Adjuvants, Immunologic; C508609:IL10 protein, human; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases