MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8.
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.
Buck Institute for Age Research, Novato, CA 94945, USA.
Dipa
D
Bhaumik
Gary K
GK
Scott
Shiruyeh
S
Schokrpur
Christopher K
CK
Patil
Arturo V
AV
Orjalo
Francis
F
Rodier
Gordon J
GJ
Lithgow
Judith
J
Campisi
D000375:Aging / Q000502:physiology*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism
D053582:Interleukin-1alpha; D015850:Interleukin-6; D016209:Interleukin-8; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D017472:Receptors, Interleukin-1; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases