FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2151392365> ?p ?o ?g. }

• W2151392365 endingPage "1723" @default.
• W2151392365 startingPage "1721" @default.
• W2151392365 abstract "See “NOD2 transgenic mice exhibit enhanced MDP-mediated down-regulation of TLR2 responses and resistance to colitis induction,” by Yang Z, Fuss IJ, Watanabe T, et al, on page 1510. See “NOD2 transgenic mice exhibit enhanced MDP-mediated down-regulation of TLR2 responses and resistance to colitis induction,” by Yang Z, Fuss IJ, Watanabe T, et al, on page 1510. The link between NOD2 and Crohn’s disease electrified the field of inflammatory bowel disease (IBD) research, and initiated the still leading impact of IBD genomics on the genetics of common disease.1Consortium W.T.C.C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7796) Google Scholar The first reports of disease-associated NOD2 alleles are now widely replicated as a susceptibility trait in ∼15% of Crohn’s disease patients of Western heritage, and a predictor of clinical phenotypes. Using powerful genome-wide association technologies and analyses, the number of new genetic loci associated with IBD abound,2Rioux J.D. Xavier R.J. Taylor K.D. et al.Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.Nat Genet. 2007; 39: 596-604Crossref PubMed Scopus (1477) Google Scholar, 3Hampe J. Franke A. Rosenstiel P. et al.A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.Nat Genet. 2007; 39: 207-211Crossref PubMed Scopus (1552) Google Scholar and several of these genes or loci interact with NOD2 to increase disease penetrance or specify clinical phenotype.4Cho J.H. Weaver C.T. The genetics of inflammatory bowel disease.Gastroenterology. 2007; 133: 1327-1339Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar This ensemble of genetic loci presents powerful insights and emphasizes the role of innate immune function and the epithelial cell stress response in the biology of disease pathogenesis. With the completion of major genome-wide association studies in other chronic inflammatory diseases, we can also perceive a shared mosaic of disease susceptibility traits, and even find optimism that they may be targeted across clinical disciplines for therapy or even prevention.1Consortium W.T.C.C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7796) Google Scholar However, I live in Los Angeles, the home of the Dodgers baseball team. So, I understand that even the most promising circumstances can lead to periods of confusion and doubt.5Danielson M.N. Home team: professional sports and the American metropolis. Princeton University Press, Princeton, NJ1997Google Scholar NOD2 is a leucine-rich repeat intracellular receptor specific for muramyl-dipeptide structures, a characteristic product of bacterial cell walls. In NOD2-bearing cells, uptake and delivery of bacterial products to NOD2 activates a robust signaling cascade that modifies acute cell behavior through biochemical crosstalk, and longer term cellular properties through transcriptional reprogramming.6Inohara N. Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis.Nat Rev Immunol. 2003; 3: 371-382Crossref PubMed Scopus (863) Google Scholar Because the disease-associated alleles attenuate NOD2 receptor activity,7Bonen D.K. Ogura Y. Nicolae D.L. et al.Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan.Gastroenterology. 2003; 124: 140-146Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar impaired NOD2-dependent control of enteric bacteria seemed to lay at the root of the disease phenotype. Indeed, NOD2 proved important for antibacterial responses of macrophages, and in the epithelial microbial response.8Hisamatsu T. Suzuki M. Reinecker H.C. et al.CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 9Wehkamp J. Salzman N.H. Porter E. et al.Reduced Paneth cell alpha-defensins in ileal Crohn’s disease.Proc Natl Acad Sci U S A. 2005; 102: 18129-18134Crossref PubMed Scopus (807) Google Scholar All was good in Mudville.10Thayer E. “Casey at the Bat,” or “A Ballad of the Republic Sung in the Year 1888”.San Francisco Examiner. 1888; : 8Google Scholar As the season of research progressed, confusion emerged. NOD2-deficient mice generally displayed normal colitis susceptibility and surprisingly subtle deficits in bacterial control.11Kobayashi K.S. Chamaillard M. Ogura Y. et al.Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.Science. 2005; 307: 731-734Crossref PubMed Scopus (1481) Google Scholar, 12Pauleau A.L. Murray P.J. Role of nod2 in the response of macrophages to toll-like receptor agonists.Mol Cell Biol. 2003; 23: 7531-7539Crossref PubMed Scopus (230) Google Scholar These findings could reflect redundancy in these critical host-protection functions, and, as in humans, the requirement for complementing alleles of other disease susceptibility loci. Then, things got worse. Two provocative studies revealed that Crohn’s disease-associated NOD2 alleles augmented rather attenuated nuclear factor (NF)-κB signaling induced by muramyl dipeptide.13Maeda S. Hsu L.C. Liu H. et al.Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing.Science. 2005; 307: 734-738Crossref PubMed Scopus (670) Google Scholar, 14Netea M.G. Ferwerda G. de Jong D.J. et al.Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release.J Immunol. 2005; 174: 6518-6523Crossref PubMed Scopus (231) Google Scholar Confusion turned to doubt: Are disease-associated NOD2 alleles attenuating or activating? A keen analysis of NOD2-deficient mice by Watanabe et al15Watanabe T. Kitani A. Murray P.J. et al.NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.Nat Immunol. 2004; 5: 800-808Crossref PubMed Scopus (699) Google Scholar offered a surprising potential explanation. That study centered on toll-like receptor (TLR)-2, a widely expressed cell-surface receptor also specific for bacterial products related to muramyl dipeptide. TLR-2 and other toll-like receptors play a variety of roles driving the antimicrobial host response, including direct activation of effector function by leukocytes and epithelial cells,16Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (667) Google Scholar and inactivation of immunoregulation that physiologically attenuate immune-mediated inflammation.17Pasare C. Medzhitov R. Toll-dependent control mechanisms of CD4 T cell activation.Immunity. 2004; 21: 733-741Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar NOD2 signaling inhibited TLR activation of NF-κB (notably its c-Rel subunit). Conversely, NOD-deficient mice displayed excess TLR-2–mediated signaling, and augmented recruitment of inflammation mediated by T helper (TH)-1–type CD4+ T cells (a population implicated in Crohn’s disease pathogenesis). These findings presented a delightfully paradoxical situation, where disease-associated alleles of NOD2 might indeed by functionally attenuated, but still promote inflammation owing to the unexpected regulatory crosstalk of NOD2 signaling in TLR-2–mediated host inflammation. The study by Yang et al18Yang Z. Fuss I.J. Watanabe T. et al.NOD2 transgenic mice exhibit enhanced MDP-mediated down-regulation of TLR2 responses and resistance to colitis induction.Gastroenterology. 2007; 133: 1510-1521Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar in this issue of Gastroenterology picks up the paradox from a reciprocal experimental perspective. The investigators transgenically engineered mice with elevated levels of normal NOD2, and tested the prediction that augmented NOD2 would suppress TLR-2–mediated host responses and colitis. Indeed, the engineered mice displayed reduced signaling (NF-κB p65/c-Rel), and a reduced interleukin-12 (p40) cytokine response to peptidoglycan, a TLR-2 ligand that contains muramyl dipeptide. This appeared to be TLR-2 selective; no such inhibition occurred with other TLR ligands, or with a TLR-2 ligand lacking NOD2-binding activity. With regard to disease susceptibility, NOD2 transgenic mice resisted formation of murine colitis elicited by both muramyl dipeptide-dependent (peptidoglycan) and -independent (trinitrobenzene sulfonic acid) agents. Finally, the investigators provided a link between these findings and human Crohn’s disease, in that delivery of the wild-type NOD2 gene, but not a homolog of the disease-associated frameshift mutation, conferred colitis resistance. This extensive study offers a new perspective endorsing the negative regulatory role of NOD2 in gut inflammatory homeostasis, and its deficiency as the locus of disease susceptibility. So, we are beyond the All-Star break, and things are looking better for the team. But what lies ahead? One limitation of this study is that the investigators manipulated NOD2 only in major histocompatibility complex (MHC)-II–expressing cells. Although this subset of leukocytes includes dendritic cells and macrophages thought to be important in the microbial response and immunoregulation, it may not address the balance of NOD2 action in the host through other cell types (such as epithelial cells), in which MHC-II expression, and TLR-2 expression and ligation, are divergent. The divergent microbial resistance and colitis susceptibility of NOD2 alleles in other recombinant mice leave open such possibilities. With respect to colitis, this study focused on either a strongly TLR-2–dependent (peptidoglycan) or TH-1–dependent (trinitrobenzene sulfonic acid) models. In that TH-17–dependent biology appears to be prevalent in mouse and human colitis,19Weaver C.T. Harrington L.E. Mangan P.R. et al.Th17: an effector CD4 T cell lineage with regulatory T cell ties.Immunity. 2006; 24: 677-688Abstract Full Text Full Text PDF PubMed Scopus (1173) Google Scholar the link between the TLR-2 and TH-17, and its modulation by NOD2, remains to be clarified. More important, we need to know whether the drive of TLR-2 signaling, and its impaired regulation by disease-associated NOD2 alleles, is a predominant factor in human Crohn’s disease. Genetic20De Jager P.L. Franchimont D. Waliszewska A. et al.The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases.Genes Immun. 2007; 8: 387-397Crossref PubMed Scopus (121) Google Scholar and biologic21Xavier R.J. Podolsky D.K. Unravelling the pathogenesis of inflammatory bowel disease.Nature. 2007; 448: 427-434Crossref PubMed Scopus (3257) Google Scholar evidence support this idea, but direct validation awaits. If so, how does crosstalk between NOD2 and TLR-2 work at the biochemical level? And, what can be done about it therapeutically? It is hard to pharmacologically restore activity of an impaired protein. However, the present study offers an encouraging proof of concept, with plasmid delivery of functional NOD2 that conferred colitis resistance. Moreover, if NOD2 acts as a negative regulator, then there is another option, namely, inhibiting activity of its downstream target. A number of agents in the pipeline interfere with TLR-2 receptor function or signaling.22Hoebe K. Jiang Z. Georgel P. et al.TLR signaling pathways: opportunities for activation and blockade in pursuit of therapy.Curr Pharm Des. 2006; 12: 4123-4134Crossref PubMed Scopus (53) Google Scholar Such agents may be well matched for investigation in Crohn’s disease patients bearing disease-associated NOD2 alleles. The confluence of strategic commitments to and by basic and clinical researchers, and their centers and consortia, put the solutions to treatment and even prevention closer at hand.23Bousvaros A. Sylvester F. Kugathasan S. et al.Challenges in pediatric inflammatory bowel disease.Inflamm Bowel Dis. 2006; 12: 885-913Crossref PubMed Scopus (107) Google Scholar, 24Sartor R.B. Blumberg R.S. Braun J. et al.CCFA microbial-host interactions workshop: highlights and key observations.Inflamm Bowel Dis. 2007; 13: 600-619Crossref PubMed Scopus (22) Google Scholar Although this may not be the year for the Dodgers,25Plaschke B. Dodgers too old (or is it young?) for this.Los Angeles Times. 2007; (September 21): D1Google Scholar NOD2 has again made the playoffs. NOD2 Transgenic Mice Exhibit Enhanced MDP-Mediated Down-Regulation of TLR2 Responses and Resistance to Colitis InductionGastroenterologyVol. 133Issue 5PreviewBackground & Aims: Mutations in the CARD15 gene encoding NOD2 are susceptibility factors in Crohn’s disease. We explored the mechanism of this susceptibility using mice that over express NOD2. Methods: Cellular and molecular responses of mice bearing an NOD2 transgene or administered plasmids that express wild-type and mutated NOD2 constructs were examined. Results: In initial studies, we showed that splenocytes from NOD2 transgenic mice as compared with littermate controls exhibit decreased interleukin (IL)-12p70 responses to peptidoglycan (PGN), a TLR2 ligand that contains muramyl dipeptide, but not other TLR ligands; in contrast, IL-12 responses to PAM3CSK4, a TLR2 ligand that does not contain muramyl dipeptide, were normal. Full-Text PDF" @default.
• W2151392365 created "2016-06-24" @default.
• W2151392365 creator A5031406053 @default.
• W2151392365 date "2007-11-01" @default.
• W2151392365 modified "2023-09-27" @default.
• W2151392365 title "A NOD to the Dodgers" @default.
• W2151392365 cites W1514224413 @default.
• W2151392365 cites W1989303754 @default.
• W2151392365 cites W1995321760 @default.
• W2151392365 cites W2011197968 @default.
• W2151392365 cites W2018542503 @default.
• W2151392365 cites W2028905039 @default.
• W2151392365 cites W2043667001 @default.
• W2151392365 cites W2049841221 @default.
• W2151392365 cites W2051007260 @default.
• W2151392365 cites W2073731887 @default.
• W2151392365 cites W2077662015 @default.
• W2151392365 cites W2078621117 @default.
• W2151392365 cites W2092160468 @default.
• W2151392365 cites W2097121808 @default.
• W2151392365 cites W2112473359 @default.
• W2151392365 cites W2122031852 @default.
• W2151392365 cites W2126880379 @default.
• W2151392365 cites W2131674777 @default.
• W2151392365 cites W2131678280 @default.
• W2151392365 cites W2134505828 @default.
• W2151392365 cites W2134783591 @default.
• W2151392365 cites W2140541855 @default.
• W2151392365 cites W2149913704 @default.
• W2151392365 cites W3215275932 @default.
• W2151392365 doi "https://doi.org/10.1053/j.gastro.2007.09.055" @default.
• W2151392365 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17983814" @default.
• W2151392365 hasPublicationYear "2007" @default.
• W2151392365 type Work @default.
• W2151392365 sameAs 2151392365 @default.
• W2151392365 citedByCount "0" @default.
• W2151392365 crossrefType "journal-article" @default.
• W2151392365 hasAuthorship W2151392365A5031406053 @default.
• W2151392365 hasBestOaLocation W21513923651 @default.
• W2151392365 hasConcept C134018914 @default.
• W2151392365 hasConcept C555293320 @default.
• W2151392365 hasConcept C55851684 @default.
• W2151392365 hasConcept C71924100 @default.
• W2151392365 hasConceptScore W2151392365C134018914 @default.
• W2151392365 hasConceptScore W2151392365C555293320 @default.
• W2151392365 hasConceptScore W2151392365C55851684 @default.
• W2151392365 hasConceptScore W2151392365C71924100 @default.
• W2151392365 hasIssue "5" @default.
• W2151392365 hasLocation W21513923651 @default.
• W2151392365 hasLocation W21513923652 @default.
• W2151392365 hasOpenAccess W2151392365 @default.
• W2151392365 hasPrimaryLocation W21513923651 @default.
• W2151392365 hasRelatedWork W1506200166 @default.
• W2151392365 hasRelatedWork W1556242672 @default.
• W2151392365 hasRelatedWork W2039318446 @default.
• W2151392365 hasRelatedWork W2048182022 @default.
• W2151392365 hasRelatedWork W2080531066 @default.
• W2151392365 hasRelatedWork W2604872355 @default.
• W2151392365 hasRelatedWork W2748952813 @default.
• W2151392365 hasRelatedWork W2899084033 @default.
• W2151392365 hasRelatedWork W3032375762 @default.
• W2151392365 hasRelatedWork W3108674512 @default.
• W2151392365 hasVolume "133" @default.
• W2151392365 isParatext "false" @default.
• W2151392365 isRetracted "false" @default.
• W2151392365 magId "2151392365" @default.
• W2151392365 workType "article" @default.