The senescence-inhibitory p53 isoform Δ133p53α represses the proinflammatory chemokine CXCL10 in progeria model mice and naturally aged mice

Abstract

Aims{Delta}133p53 is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous LmnaG609G/+). The anti-aging effect of {Delta}133p53 was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile {Delta}133p53-induced changes in cytokines and chemokines. MethodsA Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic {Delta}133p53-expressing LmnaG609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed. ResultsWe confirmed {Delta}133p53-mediated repression of serum IL-6 levels. We also found that {Delta}133p53 reduced serum levels of CXCL1, IL-1, and CXCL10. We further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) {Delta}133p53-expressing LmnaG609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic {Delta}133p53 expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and {Delta}133p53 levels was observed in human spleen tissues, suggesting physiological relevance to human aging. ConclusionCXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of {Delta}133p53.