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Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice.

ABSTRACT: High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting that elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient ((-/-)) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory markers which are affected by aging, and regulated by both estrogen and IL-6; glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), interferon gamma (IFNgamma), lipid peroxidation (MDA), and synaptic density (SNAP25) and in IL-6(-/-) and WT C57Bl/6 mice. To determine age effects we used mid-age (18months) and old-age (24months) mice, and to determine region specific effects we used the hippocampus which is impaired in dementia and the cerebellum which is unimpaired in dementia. Unexpectedly, there were no effects of IL-6 deficiency on GFAP, MDA or SNAP25 levels in females, but IL-6 deficiency was associated with lower cerebellar MBP (p<0.05) levels. Interestingly, the old-aged IL-6(-/-) males had higher GFAP and MDA levels (p<0.05) in both the hippocampus and cerebellum, in addition to a greater body weight than WT. We suggest that IL-6 is important for promoting myelin synthesis in aged females, and that drugs which inhibit the synthesis of IL-6 in males may inadvertently affect fatty acid metabolism and augment aging-related neuroinflammation.

SUBMITTER: Miller VM

PROVIDER: S-EPMC2826563 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice.

Miller V M VM Lawrence D A DA Coccaro G A GA Mondal T K TK Andrews K K Dreiem A A Seegal R F RF

Brain research 20100111

High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting that elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient ((-/-)) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory marke ...[more]

PMID: 20060814

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Project description:BackgroundA20 (TNFAIP3) is a pleiotropic NFκB-dependent gene that terminates NFκB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice.MethodsThe inflammatory status of A20 wild type (WT), HT and KO brain was determined by immunostaining, quantitative PCR, and Western blot analysis. Cytokines secretion was evaluated by ELISA. Quantitative results were statistically analyzed by ANOVA followed by a post-hoc test.ResultsTotal loss of A20 caused remarkable reactive microgliosis and astrogliosis, as determined by F4/80 and GFAP immunostaining. Glial activation correlated with significantly higher mRNA and protein levels of the pro-inflammatory molecules TNF, IL-6, and MCP-1 in cerebral cortex and hippocampus of A20 KO, as compared to WT. Basal and TNF/LPS-induced cytokine production was significantly higher in A20 deficient mouse primary astrocytes and in a mouse microglia cell line. Brain endothelium of A20 KO mice demonstrated baseline activation as shown by increased vascular immunostaining for ICAM-1 and VCAM-1, and mRNA levels of E-selectin. In addition, total loss of A20 increased basal brain oxidative/nitrosative stress, as indicated by higher iNOS and NADPH oxidase subunit gp91phox levels, correlating with increased protein nitration, gauged by nitrotyrosine immunostaining. Notably, we also observed lower neurofilaments immunostaining in A20 KO brains, suggesting higher susceptibility to axonal injury. Importantly, A20 HT brains showed an intermediate phenotype, exhibiting considerable, albeit not statistically significant, increase in markers of basal inflammation when compared to WT.ConclusionsThis is the first characterization of spontaneous neuroinflammation caused by total or partial loss of A20, suggesting its key role in maintenance of nervous tissue homeostasis, particularly control of inflammation. Remarkably, mere partial loss of A20 was sufficient to cause chronic, spontaneous low-grade cerebral inflammation, which could sensitize these animals to neurodegenerative diseases. These findings carry strong clinical relevance in that they question implication of identified A20 SNPs that lower A20 expression/function (phenocopying A20 HT mice) in the pathophysiology of neuroinflammatory diseases.

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Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice.

Publications

Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice.

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