This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pauleau, A.-L.
Right arrow Articles by Murray, P. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pauleau, A.-L.
Right arrow Articles by Murray, P. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2003, p. 7531-7539, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7531-7539.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Nod2 in the Response of Macrophages to Toll-Like Receptor Agonists

Anne-Laure Pauleau{dagger} and Peter J. Murray*

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 25 March 2003/ Returned for modification 17 June 2003/ Accepted 5 August 2003

Nod2 (CARD15) is a macrophage-specific protein containing two CARD domains, a large nucleotide binding domain and leucine-rich repeats. Human genetic studies have linked mutations in NOD2/CARD15 with Crohn's disease, although the mechanisms involved are unknown. However, Nod2 has been proposed to directly bind bacterial lipopolysaccharide (LPS) and subsequently act as an activator of NF-{kappa}B via the association of the CARD domains with Rip2/RICK/CARDIAK. This is hypothesized to constitute a pathogen recognition pathway distinct from Toll-like receptor 4-mediated recognition of LPS. Using targeted mutagenesis, we introduced a mutation to delete the CARD domains of mouse Nod2. Mice lacking Nod2 were indistinguishable from controls and showed no signs of intestinal pathology. Macrophages responded normally to multiple Toll-like receptor agonists in terms of NF-{kappa}B target activation, mitogen-activated protein kinase activation, and cytokine secretion. However, Nod2-/- mice were significantly protected in endotoxin challenge experiments, and Nod2-/- macrophages were refractory to muramyl dipeptide stimulation. These results argue that Nod2 does not play an essential, nonredundant role in the response of macrophages to bacterial products but rather plays unexpected roles in regulating systemic responses to pathogens.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495 3219. Fax: (901) 495 3099. E-mail: peter.murray{at}stjude.org.

{dagger} Present address: CNRS, UMR8125 Institut Gustave Roussy, F-94805 Villejuif, France.

Molecular and Cellular Biology, November 2003, p. 7531-7539, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7531-7539.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Petnicki-Ocwieja, T., Hrncir, T., Liu, Y.-J., Biswas, A., Hudcovic, T., Tlaskalova-Hogenova, H., Kobayashi, K. S. (2009). Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl. Acad. Sci. USA 106: 15813-15818 [Abstract] [Full Text]  
  • Rosenzweig, H. L., Galster, K. T., Planck, S. R., Rosenbaum, J. T. (2009). NOD1 Expression in the Eye and Functional Contribution to IL-1{beta}-Dependent Ocular Inflammation in Mice. IOVS 50: 1746-1753 [Abstract] [Full Text]  
  • Stroh, T., Batra, A., Glauben, R., Fedke, I., Erben, U., Kroesen, A., Heimesaat, M. M., Bereswill, S., Girardin, S., Zeitz, M., Siegmund, B. (2008). Nucleotide Oligomerization Domains 1 and 2: Regulation of Expression and Function in Preadipocytes. J. Immunol. 181: 3620-3627 [Abstract] [Full Text]  
  • Kim, J.-Y., Omori, E., Matsumoto, K., Nunez, G., Ninomiya-Tsuji, J. (2008). TAK1 Is a Central Mediator of NOD2 Signaling in Epidermal Cells. J. Biol. Chem. 283: 137-144 [Abstract] [Full Text]  
  • Gandotra, S., Jang, S., Murray, P. J., Salgame, P., Ehrt, S. (2007). Nucleotide-Binding Oligomerization Domain Protein 2-Deficient Mice Control Infection with Mycobacterium tuberculosis. Infect. Immun. 75: 5127-5134 [Abstract] [Full Text]  
  • Pan, Q., Mathison, J., Fearns, C., Kravchenko, V. V., Da Silva Correia, J., Hoffman, H. M., Kobayashi, K. S., Bertin, J., Grant, E. P., Coyle, A. J., Sutterwala, F. S., Ogura, Y., Flavell, R. A., Ulevitch, R. J. (2007). MDP-induced interleukin-1{beta} processing requires Nod2 and CIAS1/NALP3. J. Leukoc. Biol. 82: 177-183 [Abstract] [Full Text]  
  • Reiley, W. W., Jin, W., Lee, A. J., Wright, A., Wu, X., Tewalt, E. F., Leonard, T. O., Norbury, C. C., Fitzpatrick, L., Zhang, M., Sun, S.-C. (2007). Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. JEM 204: 1475-1485 [Abstract] [Full Text]  
  • Fillon, S., Soulis, K., Rajasekaran, S., Benedict-Hamilton, H., Radin, J. N., Orihuela, C. J., El Kasmi, K. C., Murti, G., Kaushal, D., Gaber, M. W., Weber, J. R., Murray, P. J., Tuomanen, E. I. (2006). Platelet-Activating Factor Receptor and Innate Immunity: Uptake of Gram-Positive Bacterial Cell Wall into Host Cells and Cell-Specific Pathophysiology. J. Immunol. 177: 6182-6191 [Abstract] [Full Text]  
  • Orihuela, C. J., Fillon, S., Smith-Sielicki, S. H., El Kasmi, K. C., Gao, G., Soulis, K., Patil, A., Murray, P. J., Tuomanen, E. I. (2006). Cell Wall-Mediated Neuronal Damage in Early Sepsis. Infect. Immun. 74: 3783-3789 [Abstract] [Full Text]  
  • Totemeyer, S., Sheppard, M., Lloyd, A., Roper, D., Dowson, C., Underhill, D., Murray, P., Maskell, D., Bryant, C. (2006). IFN-{gamma} Enhances Production of Nitric Oxide from Macrophages via a Mechanism That Depends on Nucleotide Oligomerization Domain-2.. J. Immunol. 176: 4804-4810 [Abstract] [Full Text]  
  • da Silva Correia, J., Miranda, Y., Austin-Brown, N., Hsu, J., Mathison, J., Xiang, R., Zhou, H., Li, Q., Han, J., Ulevitch, R. J. (2006). Nod1-dependent control of tumor growth. Proc. Natl. Acad. Sci. USA 103: 1840-1845 [Abstract] [Full Text]  
  • Paterson, G. K., Mitchell, T. J. (2006). Innate immunity and the pneumococcus. Microbiology 152: 285-293 [Abstract] [Full Text]  
  • Mueller, C, Macpherson, A J (2006). Layers of mutualism with commensal bacteria protect us from intestinal inflammation. Gut 55: 276-284 [Full Text]  
  • Elphick, D A, Mahida, Y R (2005). Paneth cells: their role in innate immunity and inflammatory disease. Gut 54: 1802-1809 [Full Text]  
  • Netea, M. G., Azam, T., Ferwerda, G., Girardin, S. E., Walsh, M., Park, J.-S., Abraham, E., Kim, J.-M., Yoon, D.-Y., Dinarello, C. A., Kim, S.-H. (2005). IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1{beta} and IL-6 production through a caspase 1-dependent mechanism. Proc. Natl. Acad. Sci. USA 102: 16309-16314 [Abstract] [Full Text]  
  • Watanabe, T, Kitani, A, Strober, W (2005). NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn's disease. Gut 54: 1515-1518 [Full Text]  
  • Yang, S., Takahashi, N., Yamashita, T., Sato, N., Takahashi, M., Mogi, M., Uematsu, T., Kobayashi, Y., Nakamichi, Y., Takeda, K., Akira, S., Takada, H., Udagawa, N., Furusawa, K. (2005). Muramyl Dipeptide Enhances Osteoclast Formation Induced by Lipopolysaccharide, IL-1{alpha}, and TNF-{alpha} through Nucleotide-Binding Oligomerization Domain 2-Mediated Signaling in Osteoblasts. J. Immunol. 175: 1956-1964 [Abstract] [Full Text]  
  • Cario, E (2005). BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2. Gut 54: 1182-1193 [Full Text]  
  • McDonald, C., Inohara, N., Nunez, G. (2005). Peptidoglycan Signaling in Innate Immunity and Inflammatory Disease. J. Biol. Chem. 280: 20177-20180 [Full Text]  
  • Netea, M. G., Ferwerda, G., de Jong, D. J., Jansen, T., Jacobs, L., Kramer, M., Naber, T. H. J., Drenth, J. P. H., Girardin{paragraph}, S. E., Jan Kullberg, B., Adema, G. J., Van der Meer, J. W. M. (2005). Nucleotide-Binding Oligomerization Domain-2 Modulates Specific TLR Pathways for the Induction of Cytokine Release. J. Immunol. 174: 6518-6523 [Abstract] [Full Text]  
  • Marriott, I., Rati, D. M., McCall, S. H., Tranguch, S. L. (2005). Induction of Nod1 and Nod2 Intracellular Pattern Recognition Receptors in Murine Osteoblasts following Bacterial Challenge. Infect. Immun. 73: 2967-2973 [Abstract] [Full Text]  
  • MacDonald, T. T., Monteleone, G. (2005). Immunity, Inflammation, and Allergy in the Gut. Science 307: 1920-1925 [Abstract] [Full Text]  
  • Opitz, B., Forster, S., Hocke, A. C., Maass, M., Schmeck, B., Hippenstiel, S., Suttorp, N., Krull, M. (2005). Nod1-Mediated Endothelial Cell Activation by Chlamydophila pneumoniae. Circ. Res. 96: 319-326 [Abstract] [Full Text]  
  • Maeda, S., Hsu, L.-C., Liu, H., Bankston, L. A., Iimura, M., Kagnoff, M. F., Eckmann, L., Karin, M. (2005). Nod2 Mutation in Crohn's Disease Potentiates NF-{kappa}B Activity and IL-1{beta} Processing. Science 307: 734-738 [Abstract] [Full Text]  
  • Gingras, S., Parganas, E., de Pauw, A., Ihle, J. N., Murray, P. J. (2004). Re-examination of the Role of Suppressor of Cytokine Signaling 1 (SOCS1) in the Regulation of Toll-like Receptor Signaling. J. Biol. Chem. 279: 54702-54707 [Abstract] [Full Text]  
  • Stockinger, S., Reutterer, B., Schaljo, B., Schellack, C., Brunner, S., Materna, T., Yamamoto, M., Akira, S., Taniguchi, T., Murray, P. J., Muller, M., Decker, T. (2004). IFN Regulatory Factor 3-Dependent Induction of Type I IFNs by Intracellular Bacteria Is Mediated by a TLR- and Nod2-Independent Mechanism. J. Immunol. 173: 7416-7425 [Abstract] [Full Text]  
  • Damiano, J. S., Newman, R. M., Reed, J. C. (2004). Multiple Roles of CLAN (Caspase-Associated Recruitment Domain, Leucine-Rich Repeat, and NAIP CIIA HET-E, and TP1-Containing Protein) in the Mammalian Innate Immune Response. J. Immunol. 173: 6338-6345 [Abstract] [Full Text]  
  • Opitz, B., Puschel, A., Schmeck, B., Hocke, A. C., Rosseau, S., Hammerschmidt, S., Schumann, R. R., Suttorp, N., Hippenstiel, S. (2004). Nucleotide-binding Oligomerization Domain Proteins Are Innate Immune Receptors for Internalized Streptococcus pneumoniae. J. Biol. Chem. 279: 36426-36432 [Abstract] [Full Text]  
  • Li, J., Moran, T., Swanson, E., Julian, C., Harris, J., Bonen, D. K., Hedl, M., Nicolae, D. L., Abraham, C., Cho, J. H. (2004). Regulation of IL-8 and IL-1{beta} expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 13: 1715-1725 [Abstract] [Full Text]  
  • Mathew, C. G., Lewis, C. M. (2004). Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet 13: R161-168 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»