title: The effect of NOD2 activation on TLR2-mediated cytokine responses is dependent on activation dose and NOD2 genotype.
abstract: The mechanism by which mutations in NOD2 predispose to Crohn's disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: M E A
authors.initials: ME
authors.lastname: Borm
authors.forename: A A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: C J J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: G
authors.initials: G
authors.lastname: Kraal
authors.forename: G
authors.initials: G
authors.lastname: Bouma
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D000119:Acetylmuramyl-Alanyl-Isoglutamine