Rapid Changes in MicroRNA-146a Expression Negatively Regulate the IL-1β-Induced Inflammatory Response in Human Lung Alveolar Epithelial Cells1

Posttranscriptional regulation of gene expression by microRNAs (miRNAs) has been implicated in the regulation of chronic physiological and pathological responses. In this report, we demonstrate that changes in the expression of miRNAs can also regulate acute inflammatory responses in human lung alveolar epithelial cells. Thus, stimulation with IL-1β results in a rapid time- and concentration-dependent increase in miRNA-146a and, to a lesser extent, miRNA-146b expression, although these increases were only observed at high IL-1β concentration. Examination of miRNA function by overexpression and inhibition showed that increased miRNA-146a expression negatively regulated the release of the proinflammatory chemokines IL-8 and RANTES. Subsequent examination of the mechanism demonstrated that the action of miRNA-146a was mediated at the translational level and not through the down-regulation of proteins involved in the IL-1β signaling pathway or chemokine transcription or secretion. Overall, these studies indicate that rapid increase in miRNA-146a expression provides a novel mechanism for the negative regulation of severe inflammation during the innate immune response.

[1]  Shuang Huang,et al.  Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability , 2005, Cell.

[2]  Chaoqian Xu,et al.  The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 , 2011, Nature Medicine.

[3]  Douglas K. Miller,et al.  The Interleukin-1 Receptor-associated Kinase Is Degraded by Proteasomes following Its Phosphorylation* , 1997, The Journal of Biological Chemistry.

[4]  M. Mann,et al.  Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 , 2006, Nature.

[5]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[6]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

[7]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[8]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[9]  M. Mathieu,et al.  *To whom correspondence should be addressed: , 2022 .

[10]  C. Croce,et al.  MicroRNA-133 controls cardiac hypertrophy , 2007, Nature Medicine.

[11]  Phillip D Zamore,et al.  Sequence-Specific Inhibition of Small RNA Function , 2004, PLoS biology.

[12]  Michael T. McManus,et al.  Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2 , 2007, Cell.

[13]  Martin Braddock,et al.  Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention , 2004, Nature Reviews Drug Discovery.

[14]  M. Kiriakidou,et al.  An mRNA m7G Cap Binding-like Motif within Human Ago2 Represses Translation , 2007, Cell.

[15]  N. Rajewsky,et al.  Regulation of the Germinal Center Response by MicroRNA-155 , 2007, Science.

[16]  A. Pasquinelli,et al.  MicroRNA silencing through RISC recruitment of eIF6 , 2007, Nature.

[17]  D. Baltimore,et al.  NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[18]  A. Abderrahmani,et al.  MicroRNA-9 Controls the Expression of Granuphilin/Slp4 and the Secretory Response of Insulin-producing Cells* , 2006, Journal of Biological Chemistry.

[19]  M. Lindsay,et al.  Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids , 2007, BMC Genomics.

[20]  M. Lindsay,et al.  Eosinophil but Not Neutrophil Apoptosis Caspase-catalyzed Cleavage and Activation of Mst1 Correlates With , 2022 .

[21]  Matthias W. Hentze,et al.  Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation , 2007, Nature.

[22]  Simon W. Jones,et al.  Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. , 2007, Bioconjugate chemistry.

[23]  C. Burge,et al.  The Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution , 2005, Science.

[24]  W. Filipowicz,et al.  Relief of microRNA-Mediated Translational Repression in Human Cells Subjected to Stress , 2006, Cell.

[25]  G. Stark,et al.  Interleukin-1 (IL-1) Receptor-Associated Kinase Leads to Activation of TAK1 by Inducing TAB2 Translocation in the IL-1 Signaling Pathway , 2001, Molecular and Cellular Biology.

[26]  Ola Snøve,et al.  Distance constraints between microRNA target sites dictate efficacy and cooperativity , 2007, Nucleic acids research.

[27]  Dang D. Long,et al.  Potent effect of target structure on microRNA function , 2007, Nature Structural &Molecular Biology.

[28]  W. Filipowicz,et al.  Repression of protein synthesis by miRNAs: how many mechanisms? , 2007, Trends in cell biology.

[29]  Anton J. Enright,et al.  Materials and Methods Figs. S1 to S4 Tables S1 to S5 References and Notes Micrornas Regulate Brain Morphogenesis in Zebrafish , 2022 .

[30]  Mark M. Davis,et al.  miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection , 2007, Cell.

[31]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[32]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[33]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[34]  Z. Cao,et al.  IRAK: A Kinase Associated with the Interleukin-1 Receptor , 1996, Science.

[35]  Jerry Pelletier,et al.  Short RNAs repress translation after initiation in mammalian cells. , 2006, Molecular cell.

[36]  F. Liew,et al.  Negative regulation of Toll-like receptor-mediated immune responses , 2005, Nature Reviews Immunology.

[37]  J. Steitz,et al.  AU-Rich-Element-Mediated Upregulation of Translation by FXR1 and Argonaute 2 , 2007, Cell.

[38]  Xiaoxia Li,et al.  Modulation of Toll–interleukin 1 receptor mediated signaling , 2005, Journal of Molecular Medicine.

[39]  Zihua Hu,et al.  MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. , 2008, Molecular immunology.

[40]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[41]  Ravi Jain,et al.  MicroRNA-143 Regulates Adipocyte Differentiation* , 2004, Journal of Biological Chemistry.

[42]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[43]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[44]  L. Paillard,et al.  AU-rich elements and associated factors: are there unifying principles? , 2006, Nucleic acids research.

[45]  Phillip A Sharp,et al.  siRNAs can function as miRNAs , 2003 .