NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.
The mechanism by which mutations in CARD15, which encodes nucleotide-binding oligomerization domain 2 (NOD2), cause Crohn disease is poorly understood. Because signaling via mutated NOD2 proteins leads to defective activation of the transcription factor NF-kappa B, one proposal is that mutations cause deficient NF-kappa B-dependent T helper type 1 (T(H)1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased T(H)1 responses characteristic of Crohn disease. Here we used Card15(-/-) mice to show that intact NOD2 signaling inhibited Toll-like receptor 2-driven activation of NF-kappa B, particularly of the NF-kappa B subunit c-Rel. Moreover, NOD2 deficiency or the presence of a Crohn disease-like Card15 mutation increased Toll-like receptor 2-mediated activation of NF-kappa B-c-Rel, and T(H)1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T(H)1 responses.
Watanabe
Tomohiro
T
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10 Room 11N238, 10 Center Drive, Bethesda, Maryland 20892, USA.
Kitani
Atsushi
A
Murray
Peter J
PJ
Strober
Warren
W
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors