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MicroRNAs modulate the noncanonical transcription factor NF-κB pathway by regulating expression of the kinase IKKα during macrophage differentiation

Nature Immunology volume 11, pages 799–805 (2010)Cite this article

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Abstract

MicroRNAs are key regulators of many biological processes, including cell differentiation. Here we show that during human monocyte-macrophage differentiation, expression of the microRNAs miR-223, miR-15a and miR-16 decreased considerably, which led to higher expression of the serine-threonine kinase IKKα in macrophages. In macrophages, higher IKKα expression in conjunction with stabilization of the kinase NIK induced larger amounts of p52. Because of low expression of the transcription factor RelB in untreated macrophages, high p52 expression repressed basal transcription of both canonical and noncanonical NF-κB target genes. However, proinflammatory stimuli in macrophages resulted in greater induction of noncanonical NF-κB target genes. Thus, a decrease in certain microRNAs probably prevents macrophage hyperactivation yet primes the macrophage for certain responses to proinflammatory stimuli.

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Figure 1: Upregulation of IKKα during monocyte differentiation.
Figure 2: Targeting of IKKα mRNA by miRNAs.
Figure 3: Mutation of miRNA targeting sites attenuates the inhibitory effect of miRNA mimics.
Figure 4: IKKα mRNA stability is diminished by miRNA mimics.
Figure 5: Constitutive processing of p100 to p52 in macrophages.
Figure 6: Relative contributions of IKKα and NIK to p52 demonstrated by siRNA knockdown.
Figure 7: IKKα-targeting miRNAs affect the expression of noncanonical and canonical NF-κB genes.

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Acknowledgements

We thank the Preclinical Repository of the National Cancer Institute for the antibody to the p100 C terminus and the National Institutes of Health Blood Bank for elutriated monocytes. Supported by the Intramural Research Program of The Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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  1. Tao Li and Michael J Morgan: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Tao Li, Michael J Morgan, Swati Choksi, Yan Zhang & Zheng-gang Liu

  2. Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea

    You-Sun Kim

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  1. Tao Li
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T.L. and M.J.M. contributed equally to this work and are listed alphabetically; all authors contributed throughout each stage of the development of the manuscript (conception, design, experiments and analysis).

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Correspondence to You-Sun Kim or Zheng-gang Liu.

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Li, T., Morgan, M., Choksi, S. et al. MicroRNAs modulate the noncanonical transcription factor NF-κB pathway by regulating expression of the kinase IKKα during macrophage differentiation. Nat Immunol 11, 799–805 (2010). https://doi.org/10.1038/ni.1918

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