Dataset Information

Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor ?b Activation in Preeclampsia.

ABSTRACT: Although higher nuclear factor ?B (NF?B) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NF?B activation pathways may be responsible for the higher activation of NF?B observed in preeclamptic placentas. The study included 268 cases (130 preeclamptic women and 138 controls). We studied the expression of the genes coding for NF?B activators (NIK, IKK?, IKK?, and CK2?) and inhibitors (I?B? and I?B?) using RT-PCR in real time. The RT-PCR results were verified on the protein level using ELISA and Western blot. To determine the efficiency of the pathways, the ratios of activator(s) to one of the inhibitors (I?B? or I?B?) were calculated for each studied pathway. The preeclamptic placentas demonstrated significantly lower IKK? and CK2? but higher I?B? and I?B? protein levels. In addition, the calculated activator(s) to inhibitor (I?B? or I?B?) ratios suggested that all studied pathways might be downregulated in preeclamptic placentas. Our results indicate that preeclamptic placentas may demonstrate mechanisms of NF?B activation other than the canonical, non-canonical, and atypical forms. In these mechanisms, inhibitors of NF?B may play a key role. These observations broaden the existing knowledge regarding the molecular background of preeclampsia development.

SUBMITTER: Sakowicz A

PROVIDER: S-EPMC7432517 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor кb Activation in Preeclampsia.

Sakowicz Agata A Bralewska Michalina M Pietrucha Tadeusz T Habrowska-Górczyńska Dominika E DE Piastowska-Ciesielska Agnieszka W AW Gach Agnieszka A Rybak-Krzyszkowska Magda M Witas Piotr J PJ Huras Hubert H Grzesiak Mariusz M Biesiada Lidia L

International journal of molecular sciences 20200804 15

Although higher nuclear factor κB (NFκB) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NFκB activation pathways may be responsible for the higher activation of NFκB observed in preeclamptic placentas. The study included 268 cases (130 preeclamptic women and 138 controls). We studied the expression of the genes coding for NFκB activators (NIK, IKKα, IKK ...[more]

PMID: 32759710

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Project description:Non-Hodgkin's lymphoma (NHL) is a cancer closely associated with immune function, and the tumor necrosis factor (TNF) G-308A promoter polymorphism, which influences immune function and regulation, was recently reported by the InterLymph Consortium to be associated with NHL risk. TNF signaling activates the nuclear factor-kappaB (NF-kappaB) canonical pathway, leading to transcriptional activation of multiple genes that influence inflammation and immune response. We hypothesized that, in addition to TNF signaling, common genetic variation in genes from the NF-kappaB canonical pathway may affect risk of NHL. We genotyped 54 single nucleotide polymorphisms (SNP) within TNF, lymphotoxin A LTA, and nine NF-kappaB genes from the canonical pathway (TNFRSF1A, TRADD, TRAF2, TRAF5, RIPK1, CHUK, IKBKB, NFKB1, and REL) in a clinic-based study of 441 incident cases and 475 frequency-matched controls. Tagging SNPs were selected from HapMap supplemented by putative functional SNPs for LTA/TNF. We used principal components and haplo.stats to model gene-level associations and logistic regression to model SNP-level associations. Compared with the wild-type (GG), the AA genotype for the TNF promoter polymorphism G-308A (rs1800629) was associated with increased risk of NHL [odds ratio (OR), 2.14; 95% confidence interval (95% CI), 0.94-4.85], whereas the GA genotype was not (OR, 1.00; 95% CI, 0.74-1.34). This association was similar for follicular lymphoma and diffuse large B-cell lymphoma. A previously reported LTA/TNF haplotype was also associated with NHL risk. In gene-level analysis of the NF-kappaB pathway, only NFKB1 showed a statistically significant association with NHL (P = 0.049), and one NFKB1 tagSNP (rs4648022) was associated with NHL risk overall (ordinal OR, 0.59; 95% CI, 0.41-0.84; Ptrend = 0.0037) and for each of the common subtypes. In conclusion, we provide additional evidence for the role of genetic variation in TNF and LTA SNPs and haplotypes with risk of NHL and also provide some of the first preliminary evidence for an association of genetic variation in NFKB1, a downstream target of TNF signaling, with risk of NHL.

Dataset Information

Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor ?b Activation in Preeclampsia.

Publications

Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor кb Activation in Preeclampsia.

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