Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB

Ogura, Yasunori; Inohara, Naohiro; Benito, Adalberto; Chen, Felicia F.; Shoji, Yasuhiro; Núñez, Gabriel

doi:10.1074/jbc.m008072200

Cited by 1,245 publications

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Section: Discussionsupporting

confidence: 89%

“…Subsequently, the production of the cytokines is abolished. Our quantitative data by real-time PCR, obtained in primary cells, are supported by the results obtained by other groups [36][37][38].When MNC are stimulated with low dose MDP and the TLR4 ligand LPS, a remarkable synergy in cytokine production is apparent in MNC from individuals with a intact NOD2 [9,20]. A potential role for caspase-1 in the synergy between TLR4 and NOD2 could be envisaged, since MDP can activate caspase-1 and induce IL-1b, which is known to induce IL-1b production in an autocrine fashion through stimulation of the IL-1R [21].…”

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confidence: 89%

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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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Section: Discussionsupporting

confidence: 89%

supporting

confidence: 89%

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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“…The refined Blau syndrome interval contained Ͼ80 expressed sequence tags and several known genes, including cerebellin 1 precursor (CBLN1), adenylate cyclase 7 (ADCY7), sal (Drosophila)-like 1 (SALL1), and human CARD15 (15). CARD15 (located at position 51.6 Mbp on Build 29 of NCBI Map Viewer) is a gene that appears to be strongly associated with CD in families displaying linkage to chromosome 16q (16,17).…”

Section: Resultsmentioning

confidence: 99%

CARD15 mutations in familial granulomatosis syndromes: A study of the original Blau syndrome kindred and other families with large‐vessel arteritis and cranial neuropathy

Wang¹,

Kuivaniemi²,

Bonavita³

et al. 2002

Arthritis & Rheumatism

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Objective. To analyze the CARD15 gene in families with heritable multi-organ granulomatoses, including the original Blau syndrome kindred as well as other families with related granulomatous conditions.Methods. Linkage mapping was performed in 10 families. Observed recombination events were used to exclude regions centromeric or telomeric to 16q12.1, and the Blau gene critical region was refined to <3 cM, corresponding to a physical distance of 3.5 megabasepairs. Based on its known biochemical function, CARD15 was analyzed as a positional candidate for the Blau syndrome susceptibility gene, by direct DNA sequencing.Results. These studies resulted in the identification, in 5 of the families, of 2 sequence variants at position 334 of the gene product (R334W and R334Q). Affected family members from the original Blau syndrome kindred were heterozygous for the R334W missense mutation; mutations at the same position were also observed in several unrelated Blau syndrome families, some of whose phenotypes included large-vessel arteritis and cranial neuropathy. The missense mutations segregated with the disease phenotype in the families, and were not seen in 208 control alleles.Conclusion. These findings demonstrate that CARD15 is an important susceptibility gene for Blau syndrome and for other familial granulomatoses that display phenotypic traits beyond those of classic Blau syndrome.

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“…23 CARD/NOD2 is expressed primarily in monocytes and might serve as an intracellular receptor for bacterial products transducing signals in the monocyte/macrophage leading to activation of NF B and transcription of regulatory genes. 24 Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to speculate that, apart from the IBD-associated, the sporadic colon cancer might be the consequence of bacteria-induced inflammation. 25 In addition, the localization of CARD/NOD2 in monocytes/macrophages strengthens its role in the promotion of malignancy-leading inflammatory processes, especially if one takes into account the abundance of tumor-associated macrophages and dendritic cells in the neoplasm and the surrounding stroma.…”

Section: Discussionmentioning

confidence: 99%

Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population

Papaconstantinou

Theodoropoulos

Gazouli

et al. 2004

Intl Journal of Cancer

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Epidemiological observations suggest that cancer arises from chronically inflamed tissues. Inflammatory bowel disease (IBD) is a typical example since patients with longstanding IBD are at increased risk for development of colorectal cancer (CRC). Therefore, genetic factors predisposing to or implicated in the chronic inflammatory process in IBD may simultaneously predispose to CRC. Recently CARD15/NOD2 has been associated with IBD, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the CARD15/NOD2 gene, which appear with significantly higher frequency in patients with IBD. In this report, we have examined the frequency of the 3 major mutations R702W, G908R and 3020insC of the CARD2/ NOD2 gene in a series of 104 consecutive Greek patients with sporadic colorectal cancer and 100 healthy individuals. The frequency of all the mutations was significantly elevated compared to the control population (R702W, OR‫,00.5؍‬ p‫;320.0؍‬ G908R, OR‫,87.2؍‬ p‫;520.0؍‬ 3020insC, OR‫,44.2؍‬ p‫.)710.0؍‬ Patients with advanced stage tumors were more frequently carriers of at least 1 variant in the CARD15/NOD2 gene (p‫.)900.0؍‬ Our results suggest that CARD2/NOD2 may be a genetic factor that predispose to sporadic colorectal cancer.

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Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB

Cited by 1,245 publications

References 20 publications

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

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

CARD15 mutations in familial granulomatosis syndromes: A study of the original Blau syndrome kindred and other families with large‐vessel arteritis and cranial neuropathy

Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population

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