scholarly journals Targeted Deletion of Interleukin-6 in a Mouse Model of Chronic Inflammation Demonstrates Opposing Roles in Aging: Benefit and Harm

2020 ◽  
Author(s):  
Lina Ma ◽  
Lolita S Nidadavolu ◽  
Huanle Yang ◽  
Jackie Langdon ◽  
Reyhan Westbrook ◽  
...  
Keyword(s):  
Mouse Model ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Functional Performance ◽  
Targeted Deletion ◽  
Adverse Health Outcomes ◽  
Pathway Activation ◽  
Lipid Metabolites ◽  
And Gender ◽  
Myocardial Oxidative Metabolism

Abstract Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.

scholarly journals Impaired skeletal development in interleukin-6–transgenic mice: A model for the impact of chronic inflammation on the growing skeletal system

2006 ◽  
Vol 54 (11) ◽  
pp. 3551-3563 ◽  
Author(s):  
Fabrizio De Benedetti ◽  
Nadia Rucci ◽  
Andrea Del Fattore ◽  
Barbara Peruzzi ◽  
Rita Paro ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Skeletal Development ◽  
Skeletal System ◽  
The Impact

scholarly journals Creating and validating a DNA methylation-based proxy for Interleukin-6

2020 ◽  
Author(s):  
Anna J Stevenson ◽  
Danni A Gadd ◽  
Robert Francis Hillary ◽  
Daniel L. McCartney ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Cognitive Ability ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Epigenetic Mechanism ◽  
Inverse Association ◽  
Age Related ◽  
Independent Test ◽  
Methylation Score

Chronic inflammation is a pervasive feature of ageing and may be linked to age-related cognitive decline. However, population studies evaluating its relationship with cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. The epigenetic mechanism DNA methylation has shown utility in indexing environmental exposures and could potentially be leveraged to provide proxy signatures of chronic inflammation. We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 895 older adults (mean age: 69 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (n=7,028 [417 with measured IL-6], mean age: 51 years).We examined the association between the DNA methylation IL-6 score and serum IL-6, its association with age and established correlates of circulating IL-6, and with cognitive ability. A weighted score from 12 DNA methylation sites optimally predicted IL-6 (independent test set R2=5.1%). In the independent test cohort, both measured IL-6, and the DNA methylation proxy, increased as a function of age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10-7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10-16). Serum IL-6 was not found to associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.14, SE=0.02, pFDR=1.5x10-14). These results suggest DNA methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for reliable insights into the relationship between chronic inflammation and pertinent health outcomes.

scholarly journals Creating and Validating a DNA Methylation-Based Proxy for Interleukin-6

2021 ◽  
Author(s):  
Anna J Stevenson ◽  
Danni A Gadd ◽  
Robert F Hillary ◽  
Daniel L McCartney ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Inverse Association ◽  
Generation Scotland ◽  
Independent Test ◽  
Lothian Birth Cohort ◽  
Weighted Score ◽  
The Relationship

Abstract Background Studies evaluating the relationship between chronic inflammation and cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals’ persisting levels of inflammation. DNA methylation (DNAm) has shown utility in indexing environmental exposures and could be leveraged to provide proxy signatures of chronic inflammation. Method We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 875 older adults (Lothian Birth Cohort 1936; mean age: 70 years) to develop a DNAm-based predictor. The predictor was tested in an independent cohort (Generation Scotland; N = 7028 [417 with measured IL-6], mean age: 51 years). Results A weighted score from 35 CpG sites optimally predicted IL-6 in the independent test set (Generation Scotland; R2 = 4.4%, p = 2.1 × 10−5). In the independent test cohort, both measured IL-6 and the DNAm proxy increased with age (serum IL-6: n = 417, β = 0.02, SE = 0.004, p = 1.3 × 10−7; DNAm IL-6 score: N = 7028, β = 0.02, SE = 0.0009, p &lt; 2 × 10−16). Serum IL-6 did not associate with cognitive ability (n = 417, β = −0.06, SE = 0.05, p = .19); however, an inverse association was identified between the DNAm score and cognitive functioning (N = 7028, β = −0.16, SE = 0.02, pFDR &lt; 2 × 10−16). Conclusions These results suggest methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for further insight into the relationship between inflammation and pertinent health outcomes.

Effects of dietary tryptophan supplementation in the acetic acid-induced colitis mouse model

2018 ◽  
Vol 9 (8) ◽  
pp. 4143-4152 ◽  
Author(s):  
Shuai Chen ◽  
Meiwei Wang ◽  
Lanmei Yin ◽  
Wenkai Ren ◽  
Peng Bin ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Acetic Acid ◽  
Gastrointestinal Tract ◽  
Mouse Model ◽  
Chronic Inflammation ◽  
Bowel Disease ◽  
Intestinal Immunity ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and is strongly associated with intestinal immunity and the microbiome.

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