Immunoregulatory Defects In Inflammatory Bowel Disease

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The present study explores the possibility that muramyl dipeptide (MDP) stimulation of NOD2 regulates TLR2 responses using mice expressing a NOD2 transgene in antigen-presenting cells. In initial studies we showed that stimulation of splenocytes from NOD2-transgenic mice as compared to littermate-controls (controls) exhibited greatly decreased IL-12p70 responses to peptidoglycan (PGN) a TLR2 ligand that contains MDP, but not other TLR ligands; in contrast, IL-12 responses to PAM 3CSK4, a TLR2 ligand that does not contain MDP, were normal. Similarly, transgenic mice as compared to controls exhibited greatly decreased IL-12p40 responses to IP administration of PGN but not to LPS. In further studies we showed using EMSA that PGNstimulated cells from NOD2-Tg mice exhibited greatly decreased p65 and c-Rel super-shifts, indicating decreased translocation of these components to the nucleus. Then, in a series of in vivo studies we determined the effect of NOD2 over-expression on susceptibility to induced colitis. In initial studies we found that transgenic mice bearing the NOD2 transgene were highly resistant to induction of PGN-colitis and partially resistant to induction of TNBS-colitis. Then, in complementary studies we showed that mice administered a plasmid expressing a wild-type NOD2 gene was completely resistant to TNBS-colitis whereas mice administered a plasmid expressing a NOD2 gene with the Crohns disease frame-shift mutation was only slightly resistant to TNBS-colitis. These data buttress previous evidence that wild-type NOD2 functions as an inhibitor of TLR2-induced IL-12 production whereas NOD2 resulting from a mutated NOD2 gene is a poor inhibitor of such production. As such, they provide support for the thesis that NOD2 mutations contribute to IBD by leading to excessive TLR2 cytokine responses.