<i>Nod2</i>
            Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

Maeda, Shin; Hsu, Li-Chung; Liu, Hongjun; Bankston, Laurie A.; Iimura, Mitsutoshi; Kagnoff, Martin F.; Eckmann, Lars; Karin, Michael

doi:10.1126/science.1103685

Cited by 707 publications

(540 citation statements)

References 31 publications

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“…However, macrophages from mice expressing, instead of Nod2, a murine version of the human NOD2fs, exhibit an unexpected 'gain of function' phenotype with increased NF-kB and more efficient processing and IL1-b secretion upon MDP stimulation. 107 Although these results would fit with the global increased inflammation observed in Crohn's patients, they are in discrepancy with those obtained with human NOD2fs monocytes or with macrophages from mice deficient for Nod2 that have been shown to be impaired in MDP sensing and synergy with TLRs. 85 More studies will be needed to understand these striking discrepancies.…”

Section: Nod2mentioning

confidence: 68%

“…In the case of Nod2, results from three independent groups, working on either nonbackcrossed or backcrossed animals demonstrate that Nod2 is dispensable for full TLR signaling in murine macrophages. 84,85,107 Similarly, studies from our group on macrophages from backcrossed Nod1 knockout mice reveal that Nod1 deficiency does not impair the ability to respond to TLR ligands such as LPS or lipopeptide.…”

Section: Nods/tlrmentioning

confidence: 93%

“…The results obtained by Watanabe and co-workers have been recently challenged by two groups investigating the responses of macrophages from either Nod2 knockout mice or Nod2fs knock-in mice (see also below). 85,107 While the controversy points out that the negative effect of Nod2 on TLR2-driven signaling pathways might not be a general property in every cell type, it must be noted that the two most recent studies have not investigated the Nod2/TLR2 crosstalk in CD11b þ splenocytes.…”

Section: Nods/tlrmentioning

confidence: 99%

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TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.

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Section: Nod2mentioning

confidence: 68%

Section: Nods/tlrmentioning

confidence: 93%

Section: Nods/tlrmentioning

confidence: 99%

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TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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“…Furthermore, it has to be realized that data from cell lines and overexpression models are not always compatible with data obtained from freshly isolated human cells. In addition, differences exist between NALP3 -/-mice and human cells [12,33,34], and between NOD2 -/-mice and cells obtained from Crohn's disease patients homozygous for the NOD2fs allele [7,35]. The unique role of NOD2 as key receptor of MDP for the induction of NF-jB-dependent transcription of mRNA of cytokines is underlined by showing that mRNA of IL-1b and TNF-a in NOD2fs cells is not increased after stimulation with MDP.…”

Section: Discussionmentioning

confidence: 99%

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

et al. 2007

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Synthesis and release of pro-inflammatory cytokines, such as IL-1b, play a crucial role in the intestinal inflammation that characterizes Crohn's disease. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are associated with an increased risk of Crohn's disease. Although it is known that NOD2 mediates cytokine responses to muramyl dipeptide (MDP), it is yet unclear whether NOD2 stimulation mediates only transcription of pro-IL-1b mRNA, or whether NOD2 is also involved in the activation of caspase-1 and release of active IL-1b. By investigating the response of MNC from Crohn's disease patients homozygous for the 3020insC NOD2 mutation, we were able to show that NOD2 signaling after stimulation with MDP has a dual effect by activating proIL-1b mRNA transcription and inducing release of bioactive IL-1b. Because NOD2 engagement amplifies TLR stimulation, we investigated whether activation of caspase-1 by MDP is involved in the NOD2/TLR synergism. The synergy in IL-1b production between NOD2 and TLR is mediated at post-translational level in a caspase-1-dependent manner, which indirectly suggests that NOD2 also induces caspase-1 activation. In contrast, the synergy in TNF-a production after stimulation with MDP and LPS is induced at transcriptional level. This demonstrates that both caspase-1-dependent and -independent mechanisms are involved in the synergy between NOD2 and TLR.Introduction NOD-like receptors (NLR) are intracellular receptors for bacterial peptidoglycans, which complement the recognition of pathogen-associated molecular patterns (PAMP) by membrane-bound TLR [1,2]. Nucleotide oligomerization domain 2 (NOD2) is a member of the NACHT-LRR (NLR) receptor family, which recognizes muramyl dipeptide (MDP), the minimal motif of peptidoglycan of both Gram-positive and Gram-negative bacteria [3]. Mutations in the NOD2 gene are associated with Crohn's disease [4,5], but how NOD2 exactly acts in the pathogenesis of this auto-inflammatory disease is unclear [6][7][8]. Therefore, a better understanding of the intracellular events induced by the interaction between NOD2 and peptidoglycan is crucial for both the insight into recognition of Gram-positive pathogens by the innate immune system, and for the pathogenesis of the inflammatory reactions in Crohn's disease. Activation of human mononuclear cells (MNC) by MDP leads to production of pro-inflammatory cytokines, especially IL-1b [7,9]. IL-1b is produced as pro-IL-1b a 31-34-kDa inactive form of the cytokine, which is later cleaved by caspase-1 to the bioactive 17-kDa . This is followed by IL-1b excretion in microvesicles into the extracellular environment [11]. Apparently, MDP is capable of inducing all three steps, but it is unclear whether NOD2 alone or other receptors are involved in one or more of these steps of IL-1b production. It has been proposed that several of the NLR family members are able to recognize MDP, most notably NOD2, NALP3, and NALP1, and that they execute different functions necessary for cytokine production. In this concept, ...

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“…[7][8][9] In addition, mutations in CARD15/NOD2 have been associated with susceptibility to human CD [10][11][12] and shown to affect nuclear factor-kB (NF-kB) activation, interleukin (IL)-1b processing, and resistance to intestinal Listeria monocytogenes infection in mice. 13,14 Within the TLR family of PRR, there are 10 different transmembrane receptors (TLR1-10) that are found either on the extracellular surface of cells (TLR1, 2 and 4) or within intracellular compartments such as endosomes (TLR3 and 7-9). 15 An eleventh TLR sequence (TLR11) was described after the initiation of this project and was therefore not assessed in our study; it is still unclear whether TLR11 produces a functional protein in humans.…”

Section: Introductionmentioning

confidence: 99%

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

et al. 2007

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The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P ¼ 0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P ¼ 0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P ¼ 0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway -in this case, TLR4 and its signaling molecule TIRAP -plays a role in susceptibility to IBD.

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Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

Cited by 707 publications

References 31 publications

TIR, CARD and PYRIN: three domains for an antimicrobial triad

TIR, CARD and PYRIN: three domains for an antimicrobial triad

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

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