Dataset Information

Tumor necrosis factor-? confers cardioprotection through ectopic expression of keratins K8 and K18.

ABSTRACT: Tumor necrosis factor-? (TNF-?), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-? also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-? in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-? are a consequence of nuclear factor-?B (NF-?B)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-? expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-?- and NF-?B-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.

SUBMITTER: Papathanasiou S

PROVIDER: S-EPMC5419049 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.

Papathanasiou Stamatis S Rickelt Steffen S Soriano Maria Eugenia ME Schips Tobias G TG Maier Harald J HJ Davos Constantinos H CH Varela Aimilia A Kaklamanis Loukas L Mann Douglas L DL Capetanaki Yassemi Y

Nature medicine 20150817 9

Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κ ...[more]

PMID: 26280121

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Project description:PURPOSE: This meta-analysis was performed to clarify the association between tumor necrosis factor alpha (TNF-?) gene polymorphisms and open angle glaucoma (OAG) risks, and the association between the TNF-? level in aqueous humor (AH) and the risks of glaucoma. METHODS: A computerized literature search was performed for the relevant available studies from three databases including PubMed, ISI Web of Science, and Embase. The fixed or random effect model was selected based on the heterogeneity test using the Q test and the I(2) statistic. The associations between TNF-? gene polymorphisms and OAG risks were estimated by calculating pooled odds ratios (ORs) and the 95% confidence interval (CI), while a pooled standardized mean difference with 95% CI was used for the comparison of TNF-? levels in AH between patients with OAG and controls. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 14 (1,182 cases and 3,003 controls), five (808 cases and 1,039 controls), three (645 cases and 666 controls), and three studies (404 cases and 625 controls) were finally included in the analyses for the associations between TNF-? -308G/A, -857C/T, -863C/A, and -238G/A polymorphisms and the risks of OAG, respectively. The combined results showed that the TNF-? -308G/A gene polymorphism was significantly associated with risks of high-tension glaucoma (A versus G: OR=1.660, 95% CI=1.033-2.667; AA/AG versus GG: OR=1.713, 95% CI=1.10-2.651), but not with normal tension glaucoma or exfoliation glaucoma. Ethnicity-stratified analysis revealed that a significant association also existed in Asians (A versus G: OR=1.947, 95% CI=1.097-3.456; AA/AG versus GG: OR=1.949, 95% CI=1.140-3.332). None of the other polymorphisms was significantly associated with OAG risks. Furthermore, the pooled results of six studies showed that the TNF-? levels in the AH of patients with OAG was higher than that of the control subjects (standardized mean difference=0.517, 95% CI=0.207-0.826, p=0.001). Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. CONCLUSIONS: This meta-analysis suggests that patients with OAG may have higher TNF-? levels compared with the control subjects, and the TNF-? -308G/A polymorphism is significantly associated with the risks of high-tension glaucoma. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results.

Dataset Information

Tumor necrosis factor-? confers cardioprotection through ectopic expression of keratins K8 and K18.

Publications

Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.

Similar Datasets

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