Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing.
Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.
Maeda
Shin
S
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Hsu
Li-Chung
LC
Liu
Hongjun
H
Bankston
Laurie A
LA
Iimura
Mitsutoshi
M
Kagnoff
Martin F
MF
Eckmann
Lars
L
Karin
Michael
M
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000276:immunology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D001419:Bacteria / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan / Q000276:immunology; D015398:Signal Transduction
D000900:Anti-Bacterial Agents; D016207:Cytokines; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D016264:Dextran Sulfate