title: A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation.
abstract: Although Toll-like receptor 4 (TLR4)- and nucleotide-binding oligomerization domain 2 (NOD2)-mediated signaling mechanisms have been extensively studied individually, the crosstalk between them in the regulation of intestinal mucosal defense and tissue homeostasis has been underappreciated. Here, we uncover some novel activities of NOD2 by gene expression profiling revealing the global nature of the cross-regulation between TLR4- and NOD2-mediated signaling. Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies. This balancing act is mediated through receptor-interacting serine/threonine kinase 2, and the transcriptional regulator CCAAT/enhancer-binding protein α (C/EBPα) via its serine 248 phosphorylation by Protein Kinase C. Mice deficient in C/EBPα in the hematopoietic compartment are highly susceptible to chemically induced experimental colitis in an IL-12-dependent manner. Additionally, in contrast to the dogma, we find that the major Crohn's disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense. To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240.
authors.forename: Hajeong
authors.initials: H
authors.lastname: Kim
authors.affiliation: 1] State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240 [2] Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA 10065.
authors.forename: Quanju
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240.
authors.forename: Hua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: 1] Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA 10065 [2] Department of Breast Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China 410008.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA 10065.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240 [2] Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA 10065.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D002460:Cell Line; D016000:Cluster Analysis; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D053765:Interleukin-12 Subunit p35; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D011493:Protein Kinase C