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NF-{kappa}B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

Taganov, Konstantin D. and Boldin, Mark P. and Chang, Kuang-Jung and Baltimore, David (2006) NF-{kappa}B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proceedings of the National Academy of Sciences of the United States of America, 103 (33). pp. 12481-12486. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:TAGpnas06

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Abstract

Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-{kappa}B-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3' UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.


Item Type:Article
ORCID:
AuthorORCID
Boldin, Mark P.0000-0003-4593-0669
Baltimore, David0000-0001-8723-8190
Additional Information:© 2006 by The National Academy of Sciences of the USA. Contributed by David Baltimore, June 23, 2006. Published online before print August 2, 2006, 10.1073/pnas.0605298103. We thank Joel Pomerantz for the critical reading of the manuscript and Jose Luis Riechmann, Vijaya Rao, Jaclyn Shingara, and David Brown for help with microarray work. This work was supported by National Institutes of Health Grant GM039458 and by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology. K.-J.C. was supported by Taiwan Merit Scholarship TMS-094-1-A-026. K.D.T. and M.P.B. contributed equally to this work. Author contributions: K.D.T., M.P.B., and D.B. designed research; K.D.T., M.P.B., and K.-J.C. performed research; K.D.T., M.P.B., K.-J.C., and D.B. analyzed data; and K.D.T., M.P.B., and D.B. wrote the paper. Conflict of interest statement: No conflicts declared. Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. DQ658414).
Subject Keywords:immunity; microRNA; LPS; Toll-like receptor
Record Number:CaltechAUTHORS:TAGpnas06
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:TAGpnas06
Alternative URL:http://dx.doi.org/10.1073/pnas.0605298103
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7699
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:22 Mar 2007
Last Modified:07 Nov 2017 22:29

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