Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 13, Pages 5282-5287Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810909106
Keywords
inflammation; innate immunity; Toll-like receptors; cytokines; NFKB1
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Funding
- Ministero dell'Istruzione, dell'Universita e della Ricerca
- Fondazione Cariverona
- University of Verona
- Fondazione Cariplo (NOBEL project)
- Alleanza Contro il Cancro and Istituto Superiore di Sanita (RNBIO project)
- Fondazione Humanitas per la Ricerca (Rozzano, Milan, Italy)
- Italian Association for Cancer Research
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Inflammation involves a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanisms. Recent studies have shown that microRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide noncoding RNAs, contribute to the regulation of inflammation by repressing gene expression at the posttranscriptional level. In this study, we characterize the profile of miRNAs induced by LIPS in human polymorphonuclear neutrophils (PMN) and monocytes. In particular, we identify miR-9 as the only miRNA (among 365 analyzed) up-regulated in both cell types after TLR4 activation. miR-9 is also induced by TLR2 and TLR7/8 agonists and by the proinflammatory cytokines TNF-alpha and IL-1 beta, but not by IFN gamma. Among the 3 different genes encoding miR-9 precursors in humans, we show that LIPS selectively induces the transcription of miR-9-1 located in the CROC4 locus, in a MyD88- and NF-kappa B-dependent manner. In PMN and monocytes, LPS regulates NFKB1 at both the transcriptional and posttranscriptional levels, and a conserved miR-9 seed sustained a miR-9-dependent inhibition of the NFKB1 transcript. Overall, these data suggest that TLR4-activated NF-kappa B rapidly increases the expression of miR-9 that operates a feedback control of the NF-kappa B-dependent responses by fine tuning the expression of a key member of the NF-kappa B family.
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