title: Nod2 downregulates TLR2/1 mediated IL1β gene expression in mouse peritoneal macrophages.
abstract: Nod2 is a cytosolic pattern recognition receptor. It has been implicated in many inflammatory conditions. Its signaling has been suggested to modulate TLR responses in a variety of ways, yet little is known about the mechanistic details of the process. We show in this study that Nod2 knockdown mouse peritoneal macrophages secrete more IL1β than normal macrophages when stimulated with peptidoglycan (PGN). Muramyl dipeptide (MDP, a Nod2 ligand) + PGN co-stimulated macrophages have lower expression of IL1β than PGN (TLR2/1 ligand) stimulated macrophages. MDP co-stimulation have similar effects on Pam3CSK4 (synthetic TLR2/1 ligand) mediated IL1β expression suggesting that MDP mediated down regulating effects are receptor dependent and ligand independent. MDP mediated down regulation was specific for TLR2/1 signaling as MDP does not affect LPS (TLR4 ligand) or zymosan A (TLR2/6 ligand) mediated IL1β expression. Mechanistically, MDP exerts its down regulating effects by lowering PGN/Pam3CSK4 mediated nuclear cRel levels. Lower nuclear cRel level were observed to be because of enhanced transporting back rather than reduced nuclear translocation of cRel in MDP + PGN stimulated macrophages. These results demonstrate that Nod2 and TLR2/1 signaling pathways are independent and do not interact at the level of MAPK or NF-κB activation.
authors: School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
authors: Yogesh
authors: Y
authors: Dahiya
authors: Rajeev Kumar
authors: RK
authors: Pandey
authors: Ajit
authors: A
authors: Sodhi
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D055666:Lipopeptides / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D010457:Peptidoglycan / Q000494:pharmacology; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D055666:Lipopeptides; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C508075:Pam(3)CSK(4) peptide; D010457:Peptidoglycan; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020928:Mitogen-Activated Protein Kinases