A Genome-wide Small Interfering RNA (siRNA) Screen Reveals Nuclear Factor-κB (NF-κB)-independent Regulators of NOD2-induced Interleukin-8 (IL-8) Secretion

Warner, Neil; Burberry, Aaron; Pliakas, Maria; McDonald, Christine; Núñez, Gabriel

doi:10.1074/jbc.m114.574756

Cited by 41 publications

(34 citation statements)

References 72 publications

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“…For instance, A20 was the first Ub protease identified to negatively regulate NOD2 signaling (Hitotsumatsu et al, 2008). More recently, the deubiquitinase OTULIN was shown to dampen NOD2 signaling (Fiil et al, 2013) while knockdown of the Ub-specific protease USP8 and several of it interacting partners also negatively regulate NOD2-induced interleukin-8 (CXCL8) production (Warner et al, 2014). Other roles for Ub in the regulation of NOD1 and NOD2 signaling have been revealed.…”

Section: Nod1 and Nod2 Signaling And Regulationmentioning

confidence: 99%

“…It is possible that these small molecules act directly affecting NOD protein stability, ligand recognition, and/or ATP binding and hydrolysis activity. Alternatively, they may target any one of the numerous regulatory proteins in the NOD1 and NOD2 pathway revealed by recent siRNA screens (Lipinski et al, 2012; Warner et al, 2014). …”

Section: Potential For the Therapeutic Modulation Of And Nod1 And Nodmentioning

confidence: 99%

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NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

et al. 2014

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Summary The nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce pro-inflammatory and anti-microbial responses. Here we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies suggest several mechanisms to account for the link between NOD2 mutations and susceptibility to Crohn’s disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.

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Section: Nod1 and Nod2 Signaling And Regulationmentioning

confidence: 99%

Section: Potential For the Therapeutic Modulation Of And Nod1 And Nodmentioning

confidence: 99%

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

et al. 2014

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“…It directly binds to a component of the bacterial peptidoglycan called muramyl dipeptide (MDP) which then elicits an immune response through the NF-κB pathway [17,18]. Several genes that affect NOD2 NF-κB signaling and NOD2-induced IL-8 secretion are present in loci associated with CD risk, increasing the significance of NOD2′s central role in CD [19,20]. NOD2 is the most significant therapeutic target for CD based upon its statistical prevalence, severity of the disease phenotype, and interplay with other CD-associated proteins.…”

Section: Role Of Host Genetics In Disease Predispositionmentioning

confidence: 99%

The effect of NOD2 on the microbiota in Crohn's disease

Lauro

Burch

Grimes

2016

Current Opinion in Biotechnology

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Recent advancements toward the treatment of Crohn’s disease (CD) indicate great promise for long-term remission. CD patients suffer from a complex host of dysregulated interactions between their innate immune system and microbiome. The most predominant link to the onset of CD is a genetic mutation in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (NOD2). NOD2 responds to the presence of bacteria and stimulates the immune response. Mutations to NOD2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function. Current treatments suppress the immune response rather than enhancing the function of this critical protein. New progress towards stabilizing NOD2 signaling through its interactions with chaperone proteins holds potential in the development of novel CD therapeutics.

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“…IL-6 and IL-8 can induce systemic inflammation and IL-8 can activate neutrophil granulocyte. At the same time, populations that are continuously exposed to As may chronically produce IL-8 as a result of the increases in the NF-κB mRNA levels [27]. The IL-6 and IL-8 mRNA expression by the liver tissue was significantly increased with the stimulus [28][29][30][31].…”

Section: Discussionmentioning

confidence: 98%

Arsenic Trioxide Attenuates NF-κB and Cytokine mRNA Levels in the Livers of Cocks

Zhang

Zhao

Guo

et al. 2015

Biol Trace Elem Res

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Arsenic (As) is a trace element widely found in nature. It exists in several forms, including organic arsenic, inorganic arsenic, and trivalent arsenic, the most toxic. Arsenic trioxide (As2O3) is widespread in nature. This form tends to accumulate in animals and humans and therefore has a potential harm for them. Cytokines play essential roles in the immune response and inflammation. Although the importance of cytokines in the responses to arsenic exposure has been demonstrated in many types of mammals, the function of these in poultry, especially in chickens, remains unclear. The purpose of the present study was to examine the effect of As2O3 exposure on cytokines in cock livers. In this study, 72 1-day-old male Hy-line cocks were randomly divided into four groups including the control group, low-As group, middle-As group, and high-As group. The livers were collected on days 30, 60, and 90 of the experiment. The levels of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 beta (IL-12β), and interleukin-1 beta (IL-1β) mRNA in the livers of the cocks were measured using real-time PCR. The results showed that the expression levels of IL-6, IL-8, TNF-α, and NF-κB which seemed to be a critical mediator in the inflammatory response tended to increase in the birds chronically treated with As2O3. However, the mRNA expression levels of IL-4, IL-12β, and IL-1β were decreased in the experiment. The information regarding the effects of As2O3 on cytokine mRNA expression generated in this study will be important information for arsenic toxicology evaluation.

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A Genome-wide Small Interfering RNA (siRNA) Screen Reveals Nuclear Factor-κB (NF-κB)-independent Regulators of NOD2-induced Interleukin-8 (IL-8) Secretion

Cited by 41 publications

References 72 publications

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

The effect of NOD2 on the microbiota in Crohn's disease

Arsenic Trioxide Attenuates NF-κB and Cytokine mRNA Levels in the Livers of Cocks

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