TILRR, a novel IL-1RI co-receptor, potentiates MyD88 recruitment to control Ras-dependent amplification of NF-κB.

Zhang, Xiao; Shephard, Freya; Kim, Hong B.; Palmer, Ian R.; McHarg, Selina; Fowler, Gregory J.S.; O’Neill, Luke A. J.; Kiss-Tóth, Endre; Qwarnström, Eva E.

doi:10.1074/jbc.a109.073429

Cited by 12 publications

(25 citation statements)

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“…Our earlier studies show that TILRR associates with IL-1RI to amplify IL-1-induced activation of NF-B and inflammatory genes (10). Here we demonstrate that TILRR similarly potentiates IL-1-induced anti-apoptotic responses.…”

supporting

confidence: 58%

“…Plasmid cDNAs and siRNA Constructs and TransfectionPlasmids containing wild type or mutant TILRR cDNAs, TILRR-specific or random siRNAs, wild type or mutant IL-1R1 cDNAs, dominant negative (DN) MyD88 or DNTRAF6, or the IL-8 promoter (IL-8-Luc, -EGFP) were transfected by calcium phosphate, as described previously (10), or by PolyFect (Qiagen) according to the manufacturer's instructions. All experiments used constant levels of DNA and included empty vector (mock) or random siRNA (no genomic equivalent) as controls, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Cell Culture-HeLa Cells were grown in DMEM (Invitrogen), detached using EDTA (5 mM, Sigma), and plated as described previously (10). Cells were transfected 24 h after plating and incubated with IL-1␤ (1 nM) 24 h after transfection.…”

Section: Methodsmentioning

confidence: 99%

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Distinct Control of MyD88 Adapter-dependent and Akt Kinase-regulated Responses by the Interleukin (IL)-1RI Co-receptor, TILRR

Zhang

Pino

Shephard

et al. 2012

Journal of Biological Chemistry

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Inflammatory responses are controlled through members of the interleukin-1 receptor (IL-1R)/Toll-like receptor superfamily. Our earlier work demonstrates that the IL-1 receptor type 1 (IL-1RI) co-receptor, Toll-like and IL-1 receptor regulator (TILRR), amplifies IL-1 activation of NF-κB and inflammatory genes. Here we show that TILRR similarly promotes IL-1-induced anti-apoptotic signals and reduces caspase-3 activity. Further, the TILRR-induced effects on cell survival and inflammatory responses are controlled through distinct parts of the IL-1RI regulatory Toll IL-1 receptor (TIR) domain. Alanine-scanning mutagenesis identified a functional TILRR mutant (R425A), which blocked increases in cell survival and upstream activation of Akt but had no effect on amplification of MyD88-dependent inflammatory responses. A second mutant (D448A) blocked TILRR potentiation of MyD88-dependent signals and inflammatory activation but had no impact on cell survival. Secondary structure predictions suggested that the mutations induce distinct alterations in the α-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-κB responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.

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supporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

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Distinct Control of MyD88 Adapter-dependent and Akt Kinase-regulated Responses by the Interleukin (IL)-1RI Co-receptor, TILRR

Zhang

Pino

Shephard

et al. 2012

Journal of Biological Chemistry

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“…A splice variant of FREM1, TILRR, has been shown to influence the immune response via two GAG (glycosaminoglycan) binding sites that bind to interleukin-1 receptor 1 (IL-1-R1). The binding increased MyD88 recruitment to IL-1-R1 with subsequent NF-B activation and enhanced inflammatory response (52). This isoform of FREM1 is a particularly attractive candidate for protection, as these are immunological correlates (1,2,25,30,46) to the HESN phenotype in the Pumwani cohort.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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A subgroup of women enrolled in the Pumwani sex worker cohort remain seronegative and PCR negative for human immunodeficiency virus type 1 despite repeated exposure through high-risk sex work. Studies have shown that polymorphisms of genes involved in antigen presentation and viral restriction factors are associated with resistance to HIV infection. To discover other possible genetic factors underlying this HIV-resistant phenotype, we conducted an exploratory nonbiased, low-resolution, genome-wide single-nucleotide polymorphism (SNP) analysis comparing 60 HIV-resistant women to 48 HIV-infected controls. The SNP minor allele rs1552896, in an intron of FREM1, was significantly associated with the resistant phenotype (P ‫؍‬ 1.68 ؋ 10 ؊5 ; adjusted P ‫؍‬ 2.37 ؋ 10 ؊4 ; odds ratio [OR], 9.51; 95% confidence interval [CI], 2.82 to 32.05). We expanded the sample size by genotyping rs1552896 in the Pumwani cohort and comparing 114 HIV-resistant women to 609 HIV-infected controls and confirmed the association (P ‫؍‬ 1.7 ؋ 10 ؊4 ; OR, 2.67; 95% CI, 1.47 to 4.84). To validate the association in a second cohort, we genotyped 783 women enrolled in a mother-child health study and observed the minor allele of rs1552896 enriched in HIV-uninfected women (n ‫؍‬ 488) compared to HIV-infected enrollees (n ‫؍‬ 295) (P ‫؍‬ 0.036; OR, 1.69; 95% CI, 0.98 to 2.93). Quantitative reverse transcription-PCR showed that FREM1 mRNA was highly expressed in tissues relevant for HIV-1 infection, and immunohistochemical analysis revealed that FREM1 protein is expressed in the ectocervical mucosa of HIV-resistant women. The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection.

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“…Previous studies have revealed that mechanotransduction is a physiological process that allows cells to sense and respond to mechanical stress, 38 and several molecules and receptors that have intermediary roles in mechanotransduction have been identified. 3,[39][40][41][42][43][44][45][46] One of these receptors is the Toll-like receptor-2 (TLR2), 42,43 which is expressed on the villus epithelium and on the FAE and in M cells of PPs. This receptor plays a critical role in the early, innate immunoresponse and invasion of pathogens by sensing microorganisms.…”

Section: Discussionmentioning

confidence: 99%

Histochemical and biochemical analysis of the size-dependent nanoimmunoresponse in mouse Peyer's patches using fluorescent organosilica particles

Awaad¹,

Nakamura²,

Ishimura³

2012

IJN

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Background/objective The size-dependent mucosal immunoresponse against nanomaterials (nanoimmunoresponse) is an important approach for mucosal vaccination. In the present work, the size-dependent nanoimmunoresponse of mouse Peyer’s patches (PPs) and immunoglobulin A (IgA) level was investigated using fluorescent thiol-organosilica particles. Methods Various sizes of fluorescent thiol-organosilica particles (100, 180, 365, 745, and 925 nm in diameter) were administered orally. PPs were analyzed histochemically, and IgA levels in PP homogenates, intestinal secretions around PPs, and bile were analyzed biochemically. Results When compared with the larger particles (745 and 925 nm), oral administration of smaller thiol-organosilica particles (100, 180, and 365 nm) increased the number of CD11b + macrophages and IgA + cells in the subepithelial domes of the PPs. Additionally, administration of larger particles induced the expression of alpha-L-fucose and mucosal IgA on the surface of M cells in the follicle-associated epithelia of PPs and increased the number of 33D1 + dendritic cells in the subepithelial domes of the PPs. IgA contents in the bile and PP homogenates were high after the administration of the 100 nm particles, but IgA levels in the intestinal secretions were high after the administration of the 925 nm particles. Two size-dependent routes of IgA secretions into the intestinal lumen, the enterohepatic route for smaller particles and the mucosal route for larger particles were proposed. Conclusion Thiol-organosilica particles demonstrated size-dependent nanoimmunoresponse after oral administration. The size of the particles may control the mucosal immunity in PPs and were useful in mucosal vaccination approaches.

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TILRR, a novel IL-1RI co-receptor, potentiates MyD88 recruitment to control Ras-dependent amplification of NF-κB.

Cited by 12 publications

References 0 publications

Distinct Control of MyD88 Adapter-dependent and Akt Kinase-regulated Responses by the Interleukin (IL)-1RI Co-receptor, TILRR

Distinct Control of MyD88 Adapter-dependent and Akt Kinase-regulated Responses by the Interleukin (IL)-1RI Co-receptor, TILRR

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Histochemical and biochemical analysis of the size-dependent nanoimmunoresponse in mouse Peyer's patches using fluorescent organosilica particles

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