MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8.

Authors: Bhaumik D; Scott GK; Schokrpur S; Patil CK; Orjalo AV; Rodier F; Lithgow GJ; Campisi J

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.

Keywords: Aging/*physiology; Cell Line; Fibroblasts/cytology/*metabolism; Gene Expression Regulation/physiology; Humans; Interleukin-1 Receptor-Associated Kinases/genetics/metabolism; Interleukin-1alpha/genetics/metabolism; Interleukin-6/genetics/*metabolism; Interleukin-8/genetics/*metabolism; MicroRNAs/genetics/*metabolism; Receptors, Interleukin-1/genetics/metabolism
Journal: Aging
Volume: 1
Issue: 4
Pages: 402-11
Date: Feb. 12, 2010
PMID: 20148189
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Citation:

Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, Lithgow GJ, Campisi J (2009) MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging 1: 402-11.


Lifespan Factors:
  • MIR146B microRNA 146b
  • MIR146A microRNA 146a


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