Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma

Verma, Deepti; Bivik, Cecilia; Farahani, Ensieh; Synnerstad, Ingrid; Fredrikson, Mats; Enerbäck, Charlotta; Rosdahl, Inger; Söderkvist, Peter

doi:10.1111/j.1755-148x.2012.01008.x

Cited by 104 publications

(69 citation statements)

References 49 publications

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“…The cut-off values to define high intensity of IHC staining in tumor cells were determined from Receiver Operating Characteristics curve analysis. (15,47,48). In NPC, we found that NLRP3, AIM2, and RIG-I inflammasomes were up-regulated in an NPC Affymetrix microarray database (supplemen-tal Fig.…”

Section: Methodsmentioning

confidence: 81%

Interactome-wide Analysis Identifies End-binding Protein 1 as a Crucial Component for the Speck-like Particle Formation of Activated Absence in Melanoma 2 (AIM2) Inflammasomes

Wang

Hsu

Chen

et al. 2012

Molecular & Cellular Proteomics

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Inflammasomes are cytoplasmic receptors that can recognize intracellular pathogens or danger signals and are critical for interleukin 1␤ production. Although several key components of inflammasome activation have been identified, there has not been a systematic analysis of the protein components found in the stimulated complex. In this study, we used the isobaric tags for relative and absolute quantification approach to systemically analyze the interactomes of the NLRP3, AIM2, and RIG-I inflammasomes in nasopharyngeal carcinoma cells treated with specific stimuli of these interactomes (H 2 O 2 , poly (dA:dT), and EBV noncoding RNA, respectively). We identified a number of proteins that appeared to be involved in the interactomes and also could be precipitated with antiapoptosis-associated speck-like protein containing caspase activation and recruitment domain antibodies after stimulation. Among them, end binding protein 1 was an interacting component in all three interactomes. Silencing of end binding protein 1 expression by small interfering RNA inhibited the activation of the three inflammasomes, as indicated by reduced levels of interleukin 1␤ secretion. We confirmed that end binding protein 1 directly interacted with AIM2 and ASC in vitro and in vivo. Most importantly, fluorescence confocal microscopy showed that end binding protein 1 was required for formation of the speck-like particles that represent activation of the AIM2 inflammasome. In nasopharyngeal carcinoma tissues, immunohistochemical staining showed that end binding protein 1 expression was elevated and significantly correlated with AIM2 and ASC expression in nasopharyngeal carcinoma tumor cells. In sum, we profiled the interactome components of three inflammasomes and show for the first time that end binding protein 1 is crucial for the speck-like particle formation that represents activated inflammasomes. Molecular & Cellular

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Section: Methodsmentioning

confidence: 81%

Interactome-wide Analysis Identifies End-binding Protein 1 as a Crucial Component for the Speck-like Particle Formation of Activated Absence in Melanoma 2 (AIM2) Inflammasomes

Wang

Hsu

Chen

et al. 2012

Molecular & Cellular Proteomics

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“…3A). Earlier-stage tumors present pronounced levels of inflammation: this could be due to a reaction of the innate immunity against tumorigenesis [16,26]. This condition is progressively lost after tumor establishment [11].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies demonstrate the role of NLR inflammasomes in cancer. For example, NLRP3 gene polymorphisms have been associated with melanoma [16], myeloma [17], and colorectal cancer [18]. In the present study we characterized NLR genes in urine sediments and evaluated their contribution to predict bladder cancer together with CK20.…”

Section: Introductionmentioning

confidence: 96%

Expression of inflammasome-related genes in bladder cancer and their association with cytokeratin 20 messenger RNA

Poli

Brancorsini

Cochetti

et al. 2015

Urologic Oncology: Seminars and Original Investigations

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“…This population has been used as a reference in studies of SNP distribution in Crohn's disease [253], colorectal cancer [254], sporadic malignant melanoma [255] and inflammatory disease [195].…”

Section: Healthy Individuals (Paper Iv)mentioning

confidence: 99%

Regin in Blood Immune Regulation in Type 1 Diabetes

Pihl¹

2013

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Type 1 Diabetes (T1D) is an autoimmune disease resulting in insulin deficiency as a result of autoimmune destruction of pancreatic β-cells. Preserving β-cell function in patients with T1D would be of great benefit since patients with sustained endogenous insulin secretion are known to suffer less from secondary complications due to hyperglycemia. Glutamic acid decarboxylase 65 (GAD 65 ) is a major autoantigen targeted by self-reactive lymphocytes in T1D, and has been used in several attempts at treating T1D by inducing tolerance to β-cell antigens. We showed positive clinical effects of GAD 65 formulated with aluminium hydroxide (GAD-alum) on preservation of C-peptide secretion in a phase II clinical trial. Unfortunately, a phase III clinical trial in a larger population failed to confirm this finding. Regulatory T cells (Treg) are instrumental in maintaining peripheral tolerance to self-antigens. Deficiencies in Treg function are thought to influence the pathogenesis of autoimmune diseases, including T1D. One proposed mechanism of achieving tolerance to β-cell antigens in T1D is the induction of antigen-specific Treg through immunomodulation. The general aim of this thesis was to study immune regulation in T1D, the role of Treg and immunomodulatory effects of GAD-alum treatment in particular. Our hypothesis was that Treg biology is altered in T1D and pre-diabetes, and that an induction of GAD 65 -specific Treg contributes to the clinical efficacy of GAD-alum treatment. We demonstrated that T cells expressing Treg-associated markers were increased in number in patients with recent-onset T1D, as well as in children with high risk of developing T1D. We found that antigen recall 4 years after GAD-alum treatment induced cells with both regulatory and effector phenotypes in GAD-alum treated patients. Furthermore there was no effect on Treg-mediated suppression in GAD-alum treated patients, while patients with T1D, regardless of treatment, exhibited deficient Treg-mediated suppression of Teff that was intrinsic to the Treg population. We followed patients participating in a phase III trial of GAD-alum, and using an extended antibody panel we risk, but found no effects of variant alleles on the risk of developing T1D, or on the efficacy of GAD-alum treatment. We show small effects on C-peptide secretion and autoantibody positivity in patients with T1D. In conclusion, we find that while Treg are deficient in patients with T1D, induction of Treg is an unlikely mechanism of action of GAD-alum treatment. SUPERVISOR

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Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma

Cited by 104 publications

References 49 publications

Interactome-wide Analysis Identifies End-binding Protein 1 as a Crucial Component for the Speck-like Particle Formation of Activated Absence in Melanoma 2 (AIM2) Inflammasomes

Interactome-wide Analysis Identifies End-binding Protein 1 as a Crucial Component for the Speck-like Particle Formation of Activated Absence in Melanoma 2 (AIM2) Inflammasomes

Expression of inflammasome-related genes in bladder cancer and their association with cytokeratin 20 messenger RNA

Regin in Blood Immune Regulation in Type 1 Diabetes

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