IκBβ acts to inhibit and activate gene expression during the inflammatory response (original) (raw)

• Letter
• Published: 26 August 2010
• Mathew S. Hayden1,2,
• Meixiao Long1,2,
• Martin L. Scott3 nAff5,
• A. Philip West1,
• Dekai Zhang1 nAff5,
• Andrea Oeckinghaus1,2,
• Candace Lynch4,
• Alexander Hoffmann4,
• David Baltimore3 &
• …
• Sankar Ghosh1,2

Nature volume 466, pages 1115–1119 (2010)Cite this article

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Abstract

The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major isoform of IκB, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. Although cells lacking IκBβ have been reported3,4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6,7,8,9,10,11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and c-Rel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9,10,11. Here we report that in vivo IκBβ serves both to inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-α (TNF-α). Surprisingly, absence of IκBβ results in a dramatic reduction of TNF-α in response to LPS even though activation of NF-κB is normal. The inhibition of TNF-α messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNF-α promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNF-α. As a result, IκBβ −/− mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNF-α production during the inflammatory response.

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Gene Expression Omnibus

Data deposits

The microarray data are deposited in National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE22223.

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Acknowledgements

We thank A. Lin at the Yale W.M. Keck Biostatistics Resource for analysis of microarray data. S.G. was supported by grants from the National Institutes of Health (R37-AI03343).

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Author notes

1. Ping Rao, Martin L. Scott & Dekai Zhang
   Present address: Present addresses: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033, USA (P.R.); Merck Research Laboratories, Boston, Massachusetts 02115, USA (M.L.S.); Center for Extracellular Matrix Biology, Texas A & M University Institute of Biosciences and Technology, Houston, Texas 77030, USA (D.Z.).,

Authors and Affiliations

1. Department of Immunobiology and Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
   Ping Rao, Mathew S. Hayden, Meixiao Long, A. Philip West, Dekai Zhang, Andrea Oeckinghaus & Sankar Ghosh
2. Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, 10032, New York, USA
   Mathew S. Hayden, Meixiao Long, Andrea Oeckinghaus & Sankar Ghosh
3. Department of Biology, California Institute of Technology, Pasadena, 91125, California, USA
   Martin L. Scott & David Baltimore
4. Department of Chemistry and Biochemistry, Signaling Systems Laboratory, University of California at San Diego, La Jolla, 92093, California, USA
   Candace Lynch & Alexander Hoffmann

Authors

1. Ping Rao
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2. Mathew S. Hayden
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3. Meixiao Long
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4. Martin L. Scott
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5. A. Philip West
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6. Dekai Zhang
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7. Andrea Oeckinghaus
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8. Candace Lynch
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9. Alexander Hoffmann
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10. David Baltimore
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11. Sankar Ghosh
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Contributions

P.R. characterized the mice and performed most of the experiments, M.S.H. performed the immunoprecipitation experiments and helped in writing the paper, M.L. performed collagen-induced arthritis experiments, D.Z. and A.P.W. performed generation of BMDM cells, A.O. performed some experiments, M.L.S. and D.B. generated the knockout mice, C.L. and A.H. performed the RNAse protection assays, and S.G. conceived the study and wrote the paper.

Corresponding author

Correspondence toSankar Ghosh.

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The authors declare no competing financial interests.

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Rao, P., Hayden, M., Long, M. et al. IκBβ acts to inhibit and activate gene expression during the inflammatory response.Nature 466, 1115–1119 (2010). https://doi.org/10.1038/nature09283

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• Received: 05 August 2009
• Accepted: 11 June 2010
• Issue Date: 26 August 2010
• DOI: https://doi.org/10.1038/nature09283

Editorial Summary

IκBβ functions revealed

The biological role of IκBβ, a major isoform of the IκB (inhibitor of nuclear factor-κB) family of proteins, has proved difficult to establish. Work on mice lacking IκBβ now shows that it serves a dual role, both inhibiting and facilitating the inflammatory response. IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNFα. As a result, IκBβ−/− mice are resistant to LPS-induced septic shock and collagen-induced arthritis, and therefore blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNFα production during the inflammatory response.