A miR-19 regulon that controls NF-κB signaling.
Fine-tuning of inflammatory responses by microRNAs (miRNAs) is complex, as they can both enhance and repress expression of pro-inflammatory mediators. In this study, we investigate inflammatory responses following global miRNA depletion, to better define the overall contribution of miRNAs to inflammation. We demonstrate that miRNAs positively regulate Toll-like receptor signaling using inducible Dicer1 deletion and global miRNA depletion. We establish an important contribution of miR-19b in this effect, which potentiates nuclear factor-κB (NF-κB) activity in human and mouse cells. Positive regulation of NF-κB signaling by miR-19b involves the coordinated suppression of a regulon of negative regulators of NF-κB signaling (including A20/Tnfaip3, Rnf11, Fbxl11/Kdm2a and Zbtb16). Transfection of miR-19b mimics exacerbated the inflammatory activation of rheumatoid arthritis primary fibroblast-like synoviocytes, demonstrating its physiological importance in the pathology of this disease. This study constitutes, to our knowledge, the first description of a miR-19 regulon that controls NF-κB signaling, and suggests that targeting this miRNA and linked family members could regulate the activity of NF-κB signaling in inflammation.
Centre for Cancer Research, Monash Institute of Medical Research, Clayton, Victoria 3168, Australia.
Michael P
MP
Gantier
H James
HJ
Stunden
Claire E
CE
McCoy
Mark A
MA
Behlke
Die
D
Wang
Maria
M
Kaparakis-Liaskos
Soroush T
ST
Sarvestani
Yuan H
YH
Yang
Dakang
D
Xu
Sinéad C
SC
Corr
Eric F
EF
Morand
Bryan R G
BR
Williams
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018085:Regulon; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
D018836:Inflammation Mediators; C549214:MIRN19A microRNA, human; C561642:MIRN19 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D051193:Toll-Like Receptors