Abstract
Senescence is a cellular program that irreversibly arrests the proliferation of damaged cells and induces the secretion of the inflammatory mediators IL- 6 and IL-8 which are part of a larger senescence associated secretory phenotype (SASP). We screened quiescent and senescent human fibroblasts for differentially expressed microRNAS (miRNAs) and found that miRNAs 146a and 146b (miR-146a/b) were significantly elevated during senescence. We suggest that delayed miR-146a/b induction might be a compensatory response to restrain inflammation. Indeed, ectopic expression of miR-146a/b in primary human fibroblasts suppressed IL-6 and IL-8 secretion and downregulated IRAK1, a crucial component of the IL-1 receptor signal transduction pathway. Cells undergoing senescence without induction of a robust SASP did not express miR-146a/b. Further, IL-1alpha neutralizing antibodies abolished both miR-146a/b expression and IL-6 secretion. Our findings expand the biological contexts in which miRNA-146a/b modulates inflammatory responses. They suggest that IL-1 receptor signaling initiates both miR-146a/b upregulation and cytokine secretion, and that miR-146a/b is expressed in response to rising inflammatory cytokine levels as part of a negative feedback loop that restrains excessive SASP activity.
Highlights
Cellular senescence is a cell fate program triggered by potentially oncogenic stimuli and stresses that prevent aged or abnormal cells from further proliferation [1, 2]
Manuscript in preparation), we found that miR-146a and miR-146b were expressed at significantly higher levels by senescent HCA2 cells, which are normal human fibroblasts from neonatal foreskin
In these and subsequent samples, senescence was confirmed by the low percentage of proliferating (BrdU–incorporating) cells and high percentage of cells that stained positive for the www.impactaging.com senescence associated β-galactosidase (SA- βgal) (Figure 1; Experimental Procedures)
Summary
Cellular senescence is a cell fate program triggered by potentially oncogenic stimuli and stresses that prevent aged or abnormal cells from further proliferation [1, 2]. Senescent human cells exhibit numerous changes in gene expression, many of which relate to the growth arrest [8]. Inflammation is important for development of cancer as well as many other age-related diseases [15]. Understanding the mechanisms that regulate IL-6 and IL-8 in association with senescence is important for understanding biological processes as diverse as tumor suppression and the development of age-related diseases, including cancer. MiRNAs regulate a broad range of phenotypes including embryonic development, cell proliferation, differentiation and apoptosis [24,25,26,27]. Members of the miR-34 family of miRNAs were recently shown to suppress cell proliferation and be direct targets of the p53 tumor suppressor protein which is required for the senescence growth arrest [31, 37]. In the context of the SASP, we propose that increased expression of miR146a/b serves to restrain excessive secretion of the inflammatory cytokines IL-6 and IL-8, thereby limiting senescence-associated inflammation
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