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Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.

ABSTRACT: Although preclinical data suggested that tumor necrosis factor-alpha (TNF) neutralization in heart failure (HF) would be beneficial, clinical trials of TNF antagonists were paradoxically negative. We hypothesized that TNF induces opposing inflammatory and remodeling responses in HF that are TNF-receptor (TNFR) specific.HF was induced in wild-type (WT), TNFR1(-/-), and TNFR2(-/-) mice via coronary ligation. Compared with WT HF, 4-week postinfarction survival was significantly improved in both TNFR1(-/-) and TNFR2(-/-) HF. Compared with sham, WT HF hearts exhibited significant remodeling with robust activation of nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1beta, IL-6, and IL-10. Compared with WT HF, TNFR1(-/-) HF exhibited (1) improved remodeling, hypertrophy, and contractile function; (2) less apoptosis; and (3) diminished NF-kappaB, p38 mitogen-activated protein kinase, and JNK2 activation and cytokine expression. In contrast, TNFR2(-/-) HF showed exaggerated remodeling and hypertrophy, increased border zone fibrosis, augmented NF-kappaB and p38 mitogen-activated protein kinase activation, higher IL-1beta and IL-6 gene expression, greater activated macrophages, and greater apoptosis. Oxidative stress and diastolic function were improved in both TNFR1(-/-)and TNFR2(-/-) HF. In H9c2 cardiomyocytes, sustained NF-kappaB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-kappaB activation.TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-kappaB, inflammation, and apoptosis in HF: TNFR1 exacerbates, whereas TNFR2 ameliorates, these events. However, signaling through both receptors is required to induce diastolic dysfunction and oxidative stress. TNFR-specific effects in HF should be considered when therapeutic anti-TNF strategies are developed.

SUBMITTER: Hamid T

PROVIDER: S-EPMC2730645 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.

Hamid Tariq T Gu Yan Y Ortines Roger V RV Bhattacharya Chhandashri C Wang Guangwu G Xuan Yu-Ting YT Prabhu Sumanth D SD

Circulation 20090302 10

<h4>Background</h4>Although preclinical data suggested that tumor necrosis factor-alpha (TNF) neutralization in heart failure (HF) would be beneficial, clinical trials of TNF antagonists were paradoxically negative. We hypothesized that TNF induces opposing inflammatory and remodeling responses in HF that are TNF-receptor (TNFR) specific.<h4>Methods and results</h4>HF was induced in wild-type (WT), TNFR1(-/-), and TNFR2(-/-) mice via coronary ligation. Compared with WT HF, 4-week postinfarction ...[more]

PMID: 19255345

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Project description:BackgroundCardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.MethodsA total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.ResultsWe did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG1/ATTG1 genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG1/ATTG1 more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG1 carriers.ConclusionThere is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG1/ATTG1 genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.

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

Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.

Publications

Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.

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