Interleukin 6 Knockout Inhibits Aging-Related Accumulation of p53 in the Mouse Myocardium

Bonda, Tomasz A.; Dziemidowicz, Magdalena; Cieślińska, Magdalena; Tarasiuk, Ewa; Wawrusiewicz‐Kurylonek, Natalia; Bialuk, Izabela; Winnicka, Maria M.; Kamiński, Karol

doi:10.1093/gerona/gly105

Cited by 8 publications

(8 citation statements)

References 49 publications

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“…In the current study aged IL-6KO mice demonstrated significantly decreased Mdm2 level in comparison with young adult ones, while in aged WT mice the Mdm2 was on the same level when compared with younger controls. Similarly, in our previous study performed on the mouse myocardium the expression of Mdm2 protein was lower in aged IL-6KO in comparison with young adult mice, whereas in WT control animals an agerelated decline in Mdm2 was less pronounced and did not reach the statistical threshold (Bonda et al 2019). In both studies the abundance of Mdm2 was at the same level in young adult groups.…”

Section: Discussionsupporting

confidence: 72%

“…Therefore, lack of significant effects of high p53 protein level on its cellular targets in aged WT mice may indicate that methylated p53 form constituted its majority. Moreover, our previous study evaluating significance of IL-6 deficiency in the mouse myocardium showed suppression of p53 protein accumulation in aged IL-6KO mice in comparison with WT ones, and that increased amount of p53 protein in the cardiomyocytes of aged mice expressing endogenous IL-6 constituted a cytoplasmic pool (Bonda et al 2019). This may explain why increased accumulation of p53 protein in aged animals was not accompanied by concurrent increase of its transcriptional activity.…”

Section: Discussionmentioning

confidence: 93%

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IL-6 deficiency attenuates p53 protein accumulation in aged male mouse hippocampus

et al. 2019

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Our earlier studies demonstrated slower age-related memory decline in IL-6-deficient than in control mice. Therefore, in the present study we evaluated the effect of IL-6 deficiency and aging on expression of p53, connected with accumulation of age-related cellular damages, in hippocampus of 4and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and wild type control (WT) mice. The accumulation of p53 protein in hippocampus of aged IL-6KO mice was significantly lower than in aged WT ones, while p53 mRNA level was significantly higher in IL-6-deficient mice, what indicates that the effect was independent on p53 transcription. Presence of few apoptotic cells in hippocampal dentate gyrus and lack of changes in levels of pro-apoptotic Bax, antiapoptotic Bcl-2, as well as in p21 protein in aged animals of both genotypes, points to low transcriptional activity of p53, especially in aged WT mice. Because the amount of p53 protein did not correlate with the level of Mdm2 protein, its main negative regulator, other than Mdm2dependent mechanism was involved in p53 build-up. Significantly higher mRNA levels of autophagyassociated genes: Pten, Tsc2, and Dram1 in IL-6KO mice, in conjunction with significantly lower amount of Bcl-2 protein in 4-month-old IL-6KO mice, suggests that lack of IL-6/STAT3/Bcl-2 signaling could account for better autophagy performance in these mice, preventing excessive accumulation of proteins. Taken together, attenuated p53 protein buildup, absence of enhanced apoptosis, and transcriptional up-regulation of autophagy-associated genes imply that IL-6 deficiency may protect hippocampus from age-related accumulation of cellular damages.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 93%

IL-6 deficiency attenuates p53 protein accumulation in aged male mouse hippocampus

et al. 2019

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“…36 Additionally, there is a mutual regulation mechanism between IL-6 and p53. 37 Studies have shown that p53 predominantly regulated IL-6 production and IL-6 downregulated p53 expression. 38,39 IL-6 is a pro-inflammatory cytokine, and it is elevated in the serum of patients with PD.…”

Section: ■ Introductionmentioning

confidence: 99%

Fenpropathrin Induces GLT-1 Ubiquitination and Increases IL-6 Secretion through the Mdm2-p53 Pathway

Wan

et al. 2023

ACS Chem. Neurosci.

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Human exposure to fenpropathrin, a widely used pesticide, is linked to Parkinson’s-like symptoms in the body. However, a specific pathogenic mechanism is still unclear. This study found that fenpropathrin increased the expression of murine double minute 2 (Mdm2) and reduced the expression of p53. Fenpropathrin stimulated the expression of neural precursor cell expressed, developmentally down-regulated 4-like (Nedd4L) and promoted the secretion of the inflammatory cytokine interleukin-6 (IL-6) through the Mdm2-p53 pathway. Nedd4L, a ubiquitin ligase, mediated the ubiquitination degradation of glutamate transporter 1 (GLT-1), resulting in glutamate accumulation and excitotoxicity aggravation. Our findings elucidate part of the pathogenic mechanism of fenpropathrin toxicity and provide scientific evidence to help develop guidance for pesticide control and environmental protection.

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“…As one of the most important inflammatory mediators in obesity, IL-6 was also involved in the pathogenesis of cell senescence. IL-6 KO inhibited aging-related accumulation of p53 in mouse myocardium (52). Cell senescence involves in multiple signaling pathways (53).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that the IL-6/sIL-6R complex activates the JAK/STAT3 signal transduction pathway and inhibits G1 to S phase transition of cell cycle (34,36,52). Previously, IL-6/sIL-6R induced premature senescence in normal human fibroblasts through STAT3/p53 pathway, and there was a potential binding site (5′-TTnnnnGA-3′) of p-STAT3 in the p53 promoter region (30,35).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

Xie

et al. 2021

Front. Endocrinol.

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Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

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Interleukin 6 Knockout Inhibits Aging-Related Accumulation of p53 in the Mouse Myocardium

Cited by 8 publications

References 49 publications

IL-6 deficiency attenuates p53 protein accumulation in aged male mouse hippocampus

IL-6 deficiency attenuates p53 protein accumulation in aged male mouse hippocampus

Fenpropathrin Induces GLT-1 Ubiquitination and Increases IL-6 Secretion through the Mdm2-p53 Pathway

Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

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