Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release.
The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.
Netea
Mihai G
MG
Department of Medicine, Radboud University Medical Center Nijmegen, The Netherlands. m.netea@aig.umcn.nl
Ferwerda
Gerben
G
de Jong
Dirk J
DJ
Jansen
Trees
T
Jacobs
Liesbeth
L
Kramer
Matthijs
M
Naber
Ton H J
TH
Drenth
Joost P H
JP
Girardin
Stephen E
SE
Kullberg
Bart Jan
BJ
Adema
Gosse J
GJ
Van der Meer
Jos W M
JW
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D055666:Lipopeptides; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009174:Mycoplasma / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein; D009842:Oligopeptides / Q000494:pharmacology; D010457:Peptidoglycan / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D000276:Adjuvants, Immunologic; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D055666:Lipopeptides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D009842:Oligopeptides; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; C106335:macrophage stimulatory lipopeptide 2; D003545:Cysteine